|
Compound was evaluated for mepyramine antagonism effects in guinea pig aorta (relaxation) at a mepyramine concentration of 100 nM
|
Cavia porcellus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.
Year : 2000
Volume : 43
Issue : 6
First Page : 1071
Last Page : 1084
Authors : Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W.
Abstract : A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.
|
Compound was evaluated for mepyramine antagonism effects in guinea pig ileum (contraction) at a mepyramine concentration of 100 nM
|
Cavia porcellus
|
0.7762
nM
|
|
Journal : J. Med. Chem.
Title : Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.
Year : 2000
Volume : 43
Issue : 6
First Page : 1071
Last Page : 1084
Authors : Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W.
Abstract : A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.
|
In vitro H1 agonistic activity by taking guinea pig ileum contraction
|
Cavia porcellus
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, absolute configuration, stereoselectivity, and receptor selectivity of (alpha R, beta S)-alpha,beta-dimethylhistamine, a novel high potent histamine H3 receptor agonist.
Year : 1992
Volume : 35
Issue : 23
First Page : 4434
Last Page : 4441
Authors : Lipp R, Arrang JM, Garbarg M, Luger P, Schwartz JC, Schunack W.
Abstract : Depending on the selected synthetic pathway, structural variations of the neurotransmitter histamine led to mixtures of alpha,beta-dimethylhistamines as well as to the corresponding pure optical isomers. One of these isomers, namely (alpha R,beta S)-alpha,beta-dimethylhistamine, proved to be a highly potent H3 receptor agonist with exceptional receptor selectivity. The absolute configuration of the compound was determined by X-ray structure analysis of its dihydrobromide using the anomalous dispersion of bromine. The optical purity of both enantiomers of erythro-alpha,beta-dimethylhistamine was checked by 1HNMR investigations after acylation of the amines with (R)-2-methoxy-2-phenylacetyl chloride. As expected H3 receptors distinguish in a very strong way between the title compound and its alpha S,beta R-configured enantiomer. The agonistic potency of the latter is 2 orders of magnitude lower than the potency of (alpha R,beta S)-alpha,beta-dimethylhistamine.
|
In vitro chronotropic effect of histamine at 5 ug/mL in guinea pig atrium
|
Cavia porcellus
|
980.0
nM
|
|
Journal : J. Med. Chem.
Title : Cardiotonic agents. 6. Histamine analogues as potential cardiovascular selective H2 agonists.
Year : 1990
Volume : 33
Issue : 6
First Page : 1688
Last Page : 1697
Authors : Lampe JW, Hanna RG, Piscitelli TA, Chou YL, Erhardt PW, Lumma WC, Greenberg SS, Ingebretsen WR, Marshall DC, Wiggins J.
Abstract : Twenty-six alkyl and aralkyl histamine analogues were prepared as potential cardiotonic agents. Compounds were designed to allow interaction with a putative secondary aryl binding site at the H2 receptor, the presence of which was inferred from the structure of cyprohepatadine, which is known to have H2-antagonist properties. The compounds were examined for inotropic activity in ferret papillary muscle. Potent inotropic activity was generally found in N-alkyl- and N,N-dialkylimidazole-4-ethanamines, whereas N-(amidoalkyl)imidazole-4-ethanamines and N-alkylimidazole-4-propanamines were at best weakly active. Five compounds were examined in screens designed to assess hemodynamic effects and gastric acid secretion in vivo. Two of these compounds, alpha-(3-phenyl-2-transpropenyl)-1H-imidazole-4-ethanamine and N-heptyl-1H-imidazole-4-ethanamine, showed positive inotropic activity with minimal effects on heart rate and mean arterial pressure in vivo; however, both compounds were found to stimulate gastric acid secretion. These results demonstrate that selectivity between various H2-receptor-mediated activities can be obtained with substituted histamine analogues.
|
In vitro contractile response of histamine at 0.5 ug/mL in guinea pig ileum
|
Cavia porcellus
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : Cardiotonic agents. 6. Histamine analogues as potential cardiovascular selective H2 agonists.
Year : 1990
Volume : 33
Issue : 6
First Page : 1688
Last Page : 1697
Authors : Lampe JW, Hanna RG, Piscitelli TA, Chou YL, Erhardt PW, Lumma WC, Greenberg SS, Ingebretsen WR, Marshall DC, Wiggins J.
Abstract : Twenty-six alkyl and aralkyl histamine analogues were prepared as potential cardiotonic agents. Compounds were designed to allow interaction with a putative secondary aryl binding site at the H2 receptor, the presence of which was inferred from the structure of cyprohepatadine, which is known to have H2-antagonist properties. The compounds were examined for inotropic activity in ferret papillary muscle. Potent inotropic activity was generally found in N-alkyl- and N,N-dialkylimidazole-4-ethanamines, whereas N-(amidoalkyl)imidazole-4-ethanamines and N-alkylimidazole-4-propanamines were at best weakly active. Five compounds were examined in screens designed to assess hemodynamic effects and gastric acid secretion in vivo. Two of these compounds, alpha-(3-phenyl-2-transpropenyl)-1H-imidazole-4-ethanamine and N-heptyl-1H-imidazole-4-ethanamine, showed positive inotropic activity with minimal effects on heart rate and mean arterial pressure in vivo; however, both compounds were found to stimulate gastric acid secretion. These results demonstrate that selectivity between various H2-receptor-mediated activities can be obtained with substituted histamine analogues.
|
Full pA2 value of compound at 0.3-100 nM concentration of mepyramine in guinea pig ileum
|
Cavia porcellus
|
0.8511
nM
|
|
Journal : J. Med. Chem.
Title : N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5458
Last Page : 5470
Authors : Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S.
Abstract : A novel series of N(alpha)()-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H(1)-receptor agonists. The title compounds displayed partial agonism at contractile H(1)-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H(1)-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl)ethyl]amine, N(alpha)-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H(1)-receptor agonist potency ever reported in the literature (pEC(50) 8.26, efficacy E(max) 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. N(alpha)-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC(50) 8.16, E(max) 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H(1) receptors in guinea pig aorta and potently activated H(1)-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H(2), H(3), and M(3) receptors in functional models of guinea pig. Collectively, N(alpha)-imidazolylalkyl- and N(alpha)-pyridylalkyl-substituted histaprodifens represent a novel class of potent H(1)-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H(1)-receptor and refine molecular models of H(1)-receptor activation.
|
Effective concentration for agonism activity in Endothelium-Denuded guinea pig aortic segment
|
Cavia porcellus
|
316.23
nM
|
|
Journal : J. Med. Chem.
Title : Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.
Year : 2000
Volume : 43
Issue : 6
First Page : 1071
Last Page : 1084
Authors : Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W.
Abstract : A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.
|
Effective concentration for agonism activity in guinea pig ileal whole segment
|
Cavia porcellus
|
199.53
nM
|
|
Journal : J. Med. Chem.
Title : Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.
Year : 2000
Volume : 43
Issue : 6
First Page : 1071
Last Page : 1084
Authors : Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W.
Abstract : A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.
|
Binding affinity towards histamine H3 receptor using [3H](R)-alpha-methylhistamine as radioligand in guinea pig cortical homogenates
|
Cavia porcellus
|
0.1445
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : From histamine to imidazolylalkyl-sulfonamides: the design of a novel series of histamine H3-receptor antagonists.
Year : 1999
Volume : 9
Issue : 13
First Page : 1825
Last Page : 1830
Authors : Tozer MJ, Harper EA, Kalindjian SB, Pether MJ, Shankley NP, Watt GF.
Abstract : Histamine was converted to a selective histamine H3-receptor antagonist by capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor affinity and lower variability in the data from the various bioassays were achieved with the 2-naphthalensulfonamides of histamine homologues.
|
Binding affinity towards histamine H3 receptor using [3H](R)-alpha-methylhistamine as radioligand in guinea pig ileum LMMP homogenates
|
Cavia porcellus
|
10.47
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : From histamine to imidazolylalkyl-sulfonamides: the design of a novel series of histamine H3-receptor antagonists.
Year : 1999
Volume : 9
Issue : 13
First Page : 1825
Last Page : 1830
Authors : Tozer MJ, Harper EA, Kalindjian SB, Pether MJ, Shankley NP, Watt GF.
Abstract : Histamine was converted to a selective histamine H3-receptor antagonist by capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor affinity and lower variability in the data from the various bioassays were achieved with the 2-naphthalensulfonamides of histamine homologues.
|
Inhibition of human Histamine H3 receptor using [3H]N-alpha-methyl histamine
|
Homo sapiens
|
77.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure.
Year : 2003
Volume : 46
Issue : 10
First Page : 1980
Last Page : 1988
Authors : Kazuta Y, Hirano K, Natsume K, Yamada S, Kimura R, Matsumoto S, Furuichi K, Matsuda A, Shuto S.
Abstract : A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.
|
Inhibition of the forskolin-stimulated cAMP production in SK-N-MC cells expressing human Histamine H3 receptor
|
None
|
4.074
nM
|
|
Journal : J. Med. Chem.
Title : A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine.
Year : 2003
Volume : 46
Issue : 14
First Page : 3162
Last Page : 3165
Authors : Hashimoto T, Harusawa S, Araki L, Zuiderveld OP, Smit MJ, Imazu T, Takashima S, Yamamoto Y, Sakamoto Y, Kurihara T, Leurs R, Bakker RA, Yamatodani A.
Abstract : A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.
|
Inhibitory activity determined by the inhibition of cAMP- stimulated beta-galactosidase transcription in SK-N-MC cells expressing the human Histamine H3 receptor
|
None
|
9.772
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5445
Last Page : 5457
Authors : Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, Lutz M, Spek AL, Cavoy E, Deltent MF, Menge WM, Timmerman H, Leurs R.
Abstract : Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H(3) receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H(3) receptor and the closely related H(4) receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H(3) receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H(3) receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor.
|
Histamine H3 receptor competition binding using [3H]Na-methylhistamine
|
None
|
33.88
nM
|
|
Journal : J. Med. Chem.
Title : A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine.
Year : 2003
Volume : 46
Issue : 14
First Page : 3162
Last Page : 3165
Authors : Hashimoto T, Harusawa S, Araki L, Zuiderveld OP, Smit MJ, Imazu T, Takashima S, Yamamoto Y, Sakamoto Y, Kurihara T, Leurs R, Bakker RA, Yamatodani A.
Abstract : A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.
|
Inhibitory activity measured by [3H]- N alpha- methyl-histamine binding to membranes of SK-N-MC cells expressing the human Histamine H3 receptor
|
None
|
9.333
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5445
Last Page : 5457
Authors : Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, Lutz M, Spek AL, Cavoy E, Deltent MF, Menge WM, Timmerman H, Leurs R.
Abstract : Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H(3) receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H(3) receptor and the closely related H(4) receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H(3) receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H(3) receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor.
|
Compound was evaluated for mepyramine antagonism effects in guinea pig aorta (contraction) at a mepyramine concentration of 100 nM
|
Cavia porcellus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.
Year : 2000
Volume : 43
Issue : 6
First Page : 1071
Last Page : 1084
Authors : Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W.
Abstract : A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.
|
Contractile effects antagonized by mepyramine (0.3-100 nM) against Histamine H1 receptor in guinea pig ileum
|
Cavia porcellus
|
0.8511
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N alpha-alkylated derivatives of 2-phenylhistamines: synthesis and in vitro activity of potent histamine H1-receptor agonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2583
Last Page : 2588
Authors : Kramer K, Elz S, Pertz HH, Schunack W.
Abstract : New potent N alpha-alkylated histamine H1-receptor agonists have been prepared and functionally evaluated for partial agonist potency and selectivity. N alpha-Methyl-2-(3-trifluoromethylphenyl)histamine contracts ileal segments and aortic rings of guinea-pig with a relative potency of 174% (95% confid. lim. 161-188%) and 217% (164-287%), respectively (histamine: 100%) and is the most potent H1 receptor agonist described so far.
|
Compound was tested for the contractile effects antagonized by mepyramine (1-1000 nM) against Histamine H1 receptor of guinea pig aorta.
|
Cavia porcellus
|
0.7762
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N alpha-alkylated derivatives of 2-phenylhistamines: synthesis and in vitro activity of potent histamine H1-receptor agonists.
Year : 1998
Volume : 8
Issue : 18
First Page : 2583
Last Page : 2588
Authors : Kramer K, Elz S, Pertz HH, Schunack W.
Abstract : New potent N alpha-alkylated histamine H1-receptor agonists have been prepared and functionally evaluated for partial agonist potency and selectivity. N alpha-Methyl-2-(3-trifluoromethylphenyl)histamine contracts ileal segments and aortic rings of guinea-pig with a relative potency of 174% (95% confid. lim. 161-188%) and 217% (164-287%), respectively (histamine: 100%) and is the most potent H1 receptor agonist described so far.
|
Relative potency against Histamine H1 receptor in endothelium-Denuded rings of guinea pig Aorta
|
Cavia porcellus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5458
Last Page : 5470
Authors : Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S.
Abstract : A novel series of N(alpha)()-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H(1)-receptor agonists. The title compounds displayed partial agonism at contractile H(1)-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H(1)-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl)ethyl]amine, N(alpha)-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H(1)-receptor agonist potency ever reported in the literature (pEC(50) 8.26, efficacy E(max) 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. N(alpha)-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC(50) 8.16, E(max) 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H(1) receptors in guinea pig aorta and potently activated H(1)-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H(2), H(3), and M(3) receptors in functional models of guinea pig. Collectively, N(alpha)-imidazolylalkyl- and N(alpha)-pyridylalkyl-substituted histaprodifens represent a novel class of potent H(1)-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H(1)-receptor and refine molecular models of H(1)-receptor activation.
|
Effective concentration against histamine H1 receptor in endothelium-Denuded rings of guinea pig Aorta
|
Cavia porcellus
|
162.18
nM
|
|
Journal : J. Med. Chem.
Title : N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5458
Last Page : 5470
Authors : Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S.
Abstract : A novel series of N(alpha)()-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H(1)-receptor agonists. The title compounds displayed partial agonism at contractile H(1)-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H(1)-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl)ethyl]amine, N(alpha)-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H(1)-receptor agonist potency ever reported in the literature (pEC(50) 8.26, efficacy E(max) 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. N(alpha)-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC(50) 8.16, E(max) 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H(1) receptors in guinea pig aorta and potently activated H(1)-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H(2), H(3), and M(3) receptors in functional models of guinea pig. Collectively, N(alpha)-imidazolylalkyl- and N(alpha)-pyridylalkyl-substituted histaprodifens represent a novel class of potent H(1)-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H(1)-receptor and refine molecular models of H(1)-receptor activation.
|
Effective concentration against histamine H1 receptor in guinea pig ileum
|
Cavia porcellus
|
199.53
nM
|
|
Journal : J. Med. Chem.
Title : N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5458
Last Page : 5470
Authors : Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S.
Abstract : A novel series of N(alpha)()-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H(1)-receptor agonists. The title compounds displayed partial agonism at contractile H(1)-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H(1)-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl)ethyl]amine, N(alpha)-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H(1)-receptor agonist potency ever reported in the literature (pEC(50) 8.26, efficacy E(max) 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. N(alpha)-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC(50) 8.16, E(max) 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H(1) receptors in guinea pig aorta and potently activated H(1)-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H(2), H(3), and M(3) receptors in functional models of guinea pig. Collectively, N(alpha)-imidazolylalkyl- and N(alpha)-pyridylalkyl-substituted histaprodifens represent a novel class of potent H(1)-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H(1)-receptor and refine molecular models of H(1)-receptor activation.
|
Inhibition of human Histamine H1 receptor using [3H]pyrilamine
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure.
Year : 2003
Volume : 46
Issue : 10
First Page : 1980
Last Page : 1988
Authors : Kazuta Y, Hirano K, Natsume K, Yamada S, Kimura R, Matsumoto S, Furuichi K, Matsuda A, Shuto S.
Abstract : A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.
|
Inhibitory activity against human Histamine H1 receptor
|
None
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists.
Year : 2003
Volume : 46
Issue : 26
First Page : 5812
Last Page : 5824
Authors : Govoni M, Bakker RA, van de Wetering I, Smit MJ, Menge WM, Timmerman H, Elz S, Schunack W, Leurs R.
Abstract : In the present study we searched for neutral antagonists for the human histamine H(1)-receptor (H(1)R) by screening newly synthesized ligands that are structurally related to H(1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H(1)R, histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pK(i) = 5.8, alpha = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pK(i) = 5.9, alpha = -0.09).
|
Relative potency against Histamine H1 receptor in rat aorta
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5458
Last Page : 5470
Authors : Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S.
Abstract : A novel series of N(alpha)()-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H(1)-receptor agonists. The title compounds displayed partial agonism at contractile H(1)-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H(1)-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl)ethyl]amine, N(alpha)-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H(1)-receptor agonist potency ever reported in the literature (pEC(50) 8.26, efficacy E(max) 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. N(alpha)-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC(50) 8.16, E(max) 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H(1) receptors in guinea pig aorta and potently activated H(1)-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H(2), H(3), and M(3) receptors in functional models of guinea pig. Collectively, N(alpha)-imidazolylalkyl- and N(alpha)-pyridylalkyl-substituted histaprodifens represent a novel class of potent H(1)-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H(1)-receptor and refine molecular models of H(1)-receptor activation.
|
Inhibition of human Histamine H2 receptor using [3H]tiotidine
|
Homo sapiens
|
463.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure.
Year : 2003
Volume : 46
Issue : 10
First Page : 1980
Last Page : 1988
Authors : Kazuta Y, Hirano K, Natsume K, Yamada S, Kimura R, Matsumoto S, Furuichi K, Matsuda A, Shuto S.
Abstract : A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.
|
In vitro binding affinity was measured against Histamine H3 receptor on rat cerebral cortex.
|
None
|
6.31
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine.
Year : 1999
Volume : 42
Issue : 7
First Page : 1115
Last Page : 1122
Authors : De Esch IJ, Vollinga RC, Goubitz K, Schenk H, Appelberg U, Hacksell U, Lemstra S, Zuiderveld OP, Hoffmann M, Leurs R, Menge WM, Timmerman H.
Abstract : Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD2 = 7.1; alpha = 0.75) and on guinea pig jejunum (pD2 = 6.6; alpha = 0.75). Its enantiomer, (1R, 2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H3 receptor ligands.
|
Inhibition of human Histamine H4 receptor
|
Homo sapiens
|
75.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure.
Year : 2003
Volume : 46
Issue : 10
First Page : 1980
Last Page : 1988
Authors : Kazuta Y, Hirano K, Natsume K, Yamada S, Kimura R, Matsumoto S, Furuichi K, Matsuda A, Shuto S.
Abstract : A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.
|
Inhibition of the forskolin-stimulated cAMP production in SK-N-MC cells expressing human Histamine H4 receptor
|
None
|
20.89
nM
|
|
Journal : J. Med. Chem.
Title : A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine.
Year : 2003
Volume : 46
Issue : 14
First Page : 3162
Last Page : 3165
Authors : Hashimoto T, Harusawa S, Araki L, Zuiderveld OP, Smit MJ, Imazu T, Takashima S, Yamamoto Y, Sakamoto Y, Kurihara T, Leurs R, Bakker RA, Yamatodani A.
Abstract : A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.
|
Inhibitory activity determined by the inhibition of cAMP- stimulated beta-galactosidase transcription in SK-N-MC cells expressing the human Histamine H4 receptor
|
None
|
54.95
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5445
Last Page : 5457
Authors : Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, Lutz M, Spek AL, Cavoy E, Deltent MF, Menge WM, Timmerman H, Leurs R.
Abstract : Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H(3) receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H(3) receptor and the closely related H(4) receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H(3) receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H(3) receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor.
|
Inhibition of [3H]-histamine binding to membranes of SK-N-MC cells expressing the human Histamine H4 receptor
|
Homo sapiens
|
14.45
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists.
Year : 2003
Volume : 46
Issue : 25
First Page : 5445
Last Page : 5457
Authors : Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, Lutz M, Spek AL, Cavoy E, Deltent MF, Menge WM, Timmerman H, Leurs R.
Abstract : Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H(3) receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H(3) receptor and the closely related H(4) receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H(3) receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H(3) receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor.
|
Compound was evaluated for mepyramine antagonism effects in guinea pig ileum (contraction) at a mepyramine concentration of 100 nM
|
Cavia porcellus
|
0.8511
nM
|
|
Journal : J. Med. Chem.
Title : Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.
Year : 2000
Volume : 43
Issue : 6
First Page : 1071
Last Page : 1084
Authors : Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W.
Abstract : A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.
|
In vitro H3 agonistic activity against K+ induced histamine in slices of rat brain cortex.
|
Rattus norvegicus
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, absolute configuration, stereoselectivity, and receptor selectivity of (alpha R, beta S)-alpha,beta-dimethylhistamine, a novel high potent histamine H3 receptor agonist.
Year : 1992
Volume : 35
Issue : 23
First Page : 4434
Last Page : 4441
Authors : Lipp R, Arrang JM, Garbarg M, Luger P, Schwartz JC, Schunack W.
Abstract : Depending on the selected synthetic pathway, structural variations of the neurotransmitter histamine led to mixtures of alpha,beta-dimethylhistamines as well as to the corresponding pure optical isomers. One of these isomers, namely (alpha R,beta S)-alpha,beta-dimethylhistamine, proved to be a highly potent H3 receptor agonist with exceptional receptor selectivity. The absolute configuration of the compound was determined by X-ray structure analysis of its dihydrobromide using the anomalous dispersion of bromine. The optical purity of both enantiomers of erythro-alpha,beta-dimethylhistamine was checked by 1HNMR investigations after acylation of the amines with (R)-2-methoxy-2-phenylacetyl chloride. As expected H3 receptors distinguish in a very strong way between the title compound and its alpha S,beta R-configured enantiomer. The agonistic potency of the latter is 2 orders of magnitude lower than the potency of (alpha R,beta S)-alpha,beta-dimethylhistamine.
|
Binding affinity towards human histamine H4 receptor was determined by [3H]Na-methylhistamine binding to SK-N-MC cell membranes
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of indole and benzimidazole piperazines as histamine H(4) receptor antagonists.
Year : 2004
Volume : 14
Issue : 21
First Page : 5251
Last Page : 5256
Authors : Terzioglu N, van Rijn RM, Bakker RA, De Esch IJ, Leurs R.
Abstract : We describe the structure-activity relationships for a series of ligands structurally related to the recently identified (5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (1) as histamine H(4) receptor (H(4)R) antagonists. Furthermore, we identified related benzimidazoles as novel lead compounds for the H(4)R. The ligands have been evaluated by radioligand displacement studies and functional assays for their interaction with both the human histamine H(3) and H(4) receptors and exhibit pK(i) values up to 7.5 at the human H(4)R.
|
Agonist activity at histamine H1 receptor in guinea pig ileum
|
Cavia porcellus
|
199.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Side-chain modified analogues of histaprodifen: asymmetric synthesis and histamine H1-receptor activity.
Year : 2006
Volume : 16
Issue : 3
First Page : 672
Last Page : 676
Authors : Patil R, Elz S, Reiser O.
Abstract : New analogues of histaprodifen with polar side chains have been stereoselectively synthesized and evaluated as histamine H(1)-receptor agonists. As a key transformation the asymmetric aminohydroxylation has been used, which was successfully realized for the first time on an imidazolyl derivative. While all chiral analogues proved to be weak H(1)-receptor antagonists, an achiral keto derivative of histaprodifen turned out to be the first 2-acylated histamine congener displaying partial H(1)-receptor agonism (relative potency 12%).
|
Agonist activity at human H1 receptor expressed in 293-EBNA cells by luciferase reporter gene assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure.
Year : 2006
Volume : 49
Issue : 18
First Page : 5587
Last Page : 5596
Authors : Watanabe M, Kazuta Y, Hayashi H, Yamada S, Matsuda A, Shuto S.
Abstract : The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins, especially in cases where neither the bioactive conformation nor the pharmacophore is known. To develop potent H3 and H4 receptor antagonists, a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure were designed on the basis of this strategy. These target compounds with stereochemical diversity were synthesized from the versatile chiral cyclopropane units (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (6 and 7, respectively) or their enantiomers ent-6 and ent-7. Pharmacological profiles of these conformationally restricted analogues were shown to be different depending on the cyclopropane backbones. Among the analogues, (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (11a) with the (1R)-trans-cyclopropane structure has remarkable antagonistic activity to both the H3 (Ki = 8.4 nM) and H4 (Ki = 7.6 nM) receptors. The enantiomer of 11a, i.e., ent-11a, with the (1S)-trans-cyclopropane structure turned out to be a highly potent and selective H3 receptor antagonist with a Ki of 3.6 nM. Conversely, (1R,2R)-2-[(4-chlorobenzylamino)methyl]-1-(1H-imidazol-4-yl)cyclopropane (10a) with the (1R)-trans structure was selective for the H4 receptor (Ki = 118 nM) compared to the H3 receptor (Ki > 10(3) nM). Thus, a variety of compounds with different pharmacological profiles have been developed. These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies.
|
Agonist activity at human H2 receptor expressed in 293-EBNA cells by luciferase reporter gene assay
|
Homo sapiens
|
650.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure.
Year : 2006
Volume : 49
Issue : 18
First Page : 5587
Last Page : 5596
Authors : Watanabe M, Kazuta Y, Hayashi H, Yamada S, Matsuda A, Shuto S.
Abstract : The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins, especially in cases where neither the bioactive conformation nor the pharmacophore is known. To develop potent H3 and H4 receptor antagonists, a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure were designed on the basis of this strategy. These target compounds with stereochemical diversity were synthesized from the versatile chiral cyclopropane units (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (6 and 7, respectively) or their enantiomers ent-6 and ent-7. Pharmacological profiles of these conformationally restricted analogues were shown to be different depending on the cyclopropane backbones. Among the analogues, (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (11a) with the (1R)-trans-cyclopropane structure has remarkable antagonistic activity to both the H3 (Ki = 8.4 nM) and H4 (Ki = 7.6 nM) receptors. The enantiomer of 11a, i.e., ent-11a, with the (1S)-trans-cyclopropane structure turned out to be a highly potent and selective H3 receptor antagonist with a Ki of 3.6 nM. Conversely, (1R,2R)-2-[(4-chlorobenzylamino)methyl]-1-(1H-imidazol-4-yl)cyclopropane (10a) with the (1R)-trans structure was selective for the H4 receptor (Ki = 118 nM) compared to the H3 receptor (Ki > 10(3) nM). Thus, a variety of compounds with different pharmacological profiles have been developed. These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies.
|
Agonist activity at human H3 receptor expressed in 293-EBNA cells by luciferase reporter gene assay
|
Homo sapiens
|
88.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure.
Year : 2006
Volume : 49
Issue : 18
First Page : 5587
Last Page : 5596
Authors : Watanabe M, Kazuta Y, Hayashi H, Yamada S, Matsuda A, Shuto S.
Abstract : The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins, especially in cases where neither the bioactive conformation nor the pharmacophore is known. To develop potent H3 and H4 receptor antagonists, a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure were designed on the basis of this strategy. These target compounds with stereochemical diversity were synthesized from the versatile chiral cyclopropane units (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (6 and 7, respectively) or their enantiomers ent-6 and ent-7. Pharmacological profiles of these conformationally restricted analogues were shown to be different depending on the cyclopropane backbones. Among the analogues, (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (11a) with the (1R)-trans-cyclopropane structure has remarkable antagonistic activity to both the H3 (Ki = 8.4 nM) and H4 (Ki = 7.6 nM) receptors. The enantiomer of 11a, i.e., ent-11a, with the (1S)-trans-cyclopropane structure turned out to be a highly potent and selective H3 receptor antagonist with a Ki of 3.6 nM. Conversely, (1R,2R)-2-[(4-chlorobenzylamino)methyl]-1-(1H-imidazol-4-yl)cyclopropane (10a) with the (1R)-trans structure was selective for the H4 receptor (Ki = 118 nM) compared to the H3 receptor (Ki > 10(3) nM). Thus, a variety of compounds with different pharmacological profiles have been developed. These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies.
|
Displacement of [3H]histamine from human histamine H4 receptor expressed in HEK293T cells
|
Homo sapiens
|
12.02
nM
|
|
Journal : J. Med. Chem.
Title : Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo.
Year : 2008
Volume : 51
Issue : 8
First Page : 2457
Last Page : 2467
Authors : Smits RA, Lim HD, Hanzer A, Zuiderveld OP, Guaita E, Adami M, Coruzzi G, Leurs R, de Esch IJ.
Abstract : Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H 4 receptor (H 4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline ( 3) was identified as a new lead structure for H 4R ligands. Exploration of the structure-activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1 H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.
|
Activity at human recombinant histamine H1 receptor expressed in Sf9 cells coexpressing RGS4 by steady-state GTPase activity assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.
Year : 2008
Volume : 51
Issue : 22
First Page : 7193
Last Page : 7204
Authors : Ghorai P, Kraus A, Keller M, Götte C, Igel P, Schneider E, Schnell D, Bernhardt G, Dove S, Zabel M, Elz S, Seifert R, Buschauer A.
Abstract : N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.
|
Activity at human recombinant histamine H3 receptor expressed in Sf9 cells coexpressing Galphai, G-beta-1-gamma-2 and RGS4 by steady-state GTPase activity assay
|
Homo sapiens
|
25.1
nM
|
|
Journal : J. Med. Chem.
Title : Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.
Year : 2008
Volume : 51
Issue : 22
First Page : 7193
Last Page : 7204
Authors : Ghorai P, Kraus A, Keller M, Götte C, Igel P, Schneider E, Schnell D, Bernhardt G, Dove S, Zabel M, Elz S, Seifert R, Buschauer A.
Abstract : N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.
|
Activity at human recombinant histamine H4 receptor-RGS4 fusion protein expressed in Sf9 cells coexpressing Galphai2 and G-beta-1-gamma-2 by steady-state GTPase activity assay
|
Homo sapiens
|
11.6
nM
|
|
Journal : J. Med. Chem.
Title : Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.
Year : 2008
Volume : 51
Issue : 22
First Page : 7193
Last Page : 7204
Authors : Ghorai P, Kraus A, Keller M, Götte C, Igel P, Schneider E, Schnell D, Bernhardt G, Dove S, Zabel M, Elz S, Seifert R, Buschauer A.
Abstract : N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
4.1
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Displacement of [3H]histamine from human histamine H4 receptor expressed in SK-NM-C cells
|
Homo sapiens
|
13.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening.
Year : 2008
Volume : 51
Issue : 11
First Page : 3145
Last Page : 3153
Authors : Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, Noszál B, Falus A, Keseru GM.
Abstract : A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were tested by radioligand binding assay and 16 of them possessed significant [(3)H]histamine displacement. Several novel scaffolds were identified that can be used to develop selective H4 ligands in the future. As far as we know, this is the first SBVS reported on H4R, representing one of the largest virtual screens validated by the biological evaluation of the virtual hits.
|
Agonist activity at human H1 receptor expressed in insect Sf9 cells co-expressing RGS4 assessed as gamma[32P]GTP binding by liquid scintillation counting
|
Homo sapiens
|
190.55
nM
|
|
Journal : J. Med. Chem.
Title : N(G)-acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent.
Year : 2009
Volume : 52
Issue : 8
First Page : 2623
Last Page : 2627
Authors : Igel P, Schneider E, Schnell D, Elz S, Seifert R, Buschauer A.
Abstract : 3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H(3) receptor (hH(3)R) and human histamine H(4) receptor (hH(4)R). With the aim to increase selectivity for the hH(4)R, the guanidine group in 4 was acylated. N(1)-Acetyl-N(2)-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at the hH(4)R (pEC(50) = 8.31; alpha = 1.00), possessing more than 1000- and 100-fold selectivity relative to the hH(1)R and hH(2)R, respectively, and possessing only low intrinsic activity (alpha = 0.27) at the hH(3)R.
|
Agonist activity at human H3 receptor expressed in insect Sf9 cells co-expressing Gialpha2, Gbeta1gamma2 and RGS4 assessed as gamma[32P]GTP binding by liquid scintillation counting
|
Homo sapiens
|
25.12
nM
|
|
Journal : J. Med. Chem.
Title : N(G)-acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent.
Year : 2009
Volume : 52
Issue : 8
First Page : 2623
Last Page : 2627
Authors : Igel P, Schneider E, Schnell D, Elz S, Seifert R, Buschauer A.
Abstract : 3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H(3) receptor (hH(3)R) and human histamine H(4) receptor (hH(4)R). With the aim to increase selectivity for the hH(4)R, the guanidine group in 4 was acylated. N(1)-Acetyl-N(2)-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at the hH(4)R (pEC(50) = 8.31; alpha = 1.00), possessing more than 1000- and 100-fold selectivity relative to the hH(1)R and hH(2)R, respectively, and possessing only low intrinsic activity (alpha = 0.27) at the hH(3)R.
|
Agonist activity at human H4 receptor expressed in insect Sf9 cells co-expressing RGS19 fusion protein and Gialpha2, Gbeta1gamma2 assessed as gamma[32P]GTP binding by liquid scintillation counting
|
Homo sapiens
|
12.02
nM
|
|
Journal : J. Med. Chem.
Title : N(G)-acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent.
Year : 2009
Volume : 52
Issue : 8
First Page : 2623
Last Page : 2627
Authors : Igel P, Schneider E, Schnell D, Elz S, Seifert R, Buschauer A.
Abstract : 3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H(3) receptor (hH(3)R) and human histamine H(4) receptor (hH(4)R). With the aim to increase selectivity for the hH(4)R, the guanidine group in 4 was acylated. N(1)-Acetyl-N(2)-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at the hH(4)R (pEC(50) = 8.31; alpha = 1.00), possessing more than 1000- and 100-fold selectivity relative to the hH(1)R and hH(2)R, respectively, and possessing only low intrinsic activity (alpha = 0.27) at the hH(3)R.
|
Displacement of 3-([1,1,1-3H]methyl)-2-(4-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-4(3H)-quinazolinone from mouse histamine H3 receptor expressed in HEK293 cells
|
Mus musculus
|
68.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of a selective and potent radioactive ligand for histamine H(3) receptors: A compound potentially useful for receptor occupancy studies.
Year : 2009
Volume : 19
Issue : 15
First Page : 4075
Last Page : 4078
Authors : Mitobe Y, Ito S, Mizutani T, Nagase T, Sato N, Tokita S.
Abstract : Radioligands are powerful tools for examining the pharmacological profiles of chemical leads and thus facilitate drug discovery. In this study, we identified and characterized 3-([1,1,1-(3)H]methyl)-2-(4-{[3-(1-pyrrolidinyl)propyl]oxy} phenyl)-4(3H)-quinazolinone ([(3)H]1) as a potent and selective radioligand for histamine H(3) receptors. Radioligand [(3)H]1 exhibited appreciable specific signal in brain slices prepared from wild-type mice but not from histamine H(3) receptor-deficient mice, demonstrating the specificity and utility of [(3)H]1 as a selective histamine H(3) receptor radioligand for ex-vivo receptor occupancy assays.
|
Agonist activity at human histamine H4 receptor expressed in Sf9 cells co-expressing Galphai2 and Gbeta1gamma2 assessed as stimulation of [35S]GTPgammaS binding
|
Homo sapiens
|
13.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization.
Year : 2009
Volume : 17
Issue : 20
First Page : 7186
Last Page : 7196
Authors : Sander K, Kottke T, Tanrikulu Y, Proschak E, Weizel L, Schneider EH, Seifert R, Schneider G, Stark H.
Abstract : The human histamine H(4) receptor (hH(4)R) is a promising new target in the therapy of inflammatory diseases and disorders of the immune system. For the development of new H(4)R antagonists a broad ligand-based virtual screening was performed resulting in two hits. The dissection of their common annelated aromatic core into its heteromonocyclic components showed that 2,4-diaminopyrimidine is a potent hH(4)R affinity scaffold, which was comprehensively investigated. Structure-activity relationship studies revealed that slight structural changes evoke extensive differences in functional activities and potencies: while o- and p-substituted benzyl amines mainly showed partial agonism, m-substituted and rigidified ones exhibited inverse agonist efficacy.
|
Agonist activity at human histamine H4 receptor expressed in Sf9 cells co-expressing Galphai2 and Gbeta1gamma2 assessed as stimulation of GTPase by [gamma-32P]GTP spontaneous degradation assay
|
Homo sapiens
|
11.75
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization.
Year : 2009
Volume : 17
Issue : 20
First Page : 7186
Last Page : 7196
Authors : Sander K, Kottke T, Tanrikulu Y, Proschak E, Weizel L, Schneider EH, Seifert R, Schneider G, Stark H.
Abstract : The human histamine H(4) receptor (hH(4)R) is a promising new target in the therapy of inflammatory diseases and disorders of the immune system. For the development of new H(4)R antagonists a broad ligand-based virtual screening was performed resulting in two hits. The dissection of their common annelated aromatic core into its heteromonocyclic components showed that 2,4-diaminopyrimidine is a potent hH(4)R affinity scaffold, which was comprehensively investigated. Structure-activity relationship studies revealed that slight structural changes evoke extensive differences in functional activities and potencies: while o- and p-substituted benzyl amines mainly showed partial agonism, m-substituted and rigidified ones exhibited inverse agonist efficacy.
|
Displacement of [3H]histamine from human histamine H4 receptor expressed in HEK293T cells
|
Homo sapiens
|
12.02
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists.
Year : 2010
Volume : 53
Issue : 6
First Page : 2390
Last Page : 2400
Authors : Smits RA, Adami M, Istyastono EP, Zuiderveld OP, van Dam CM, de Kanter FJ, Jongejan A, Coruzzi G, Leurs R, de Esch IJ.
Abstract : Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
|
Agonist activity at human histamine H1 receptor expressed in Sf9 cells coexpressing RGS4 by steady-state GTPase assay
|
Homo sapiens
|
190.55
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists.
Year : 2009
Volume : 52
Issue : 20
First Page : 6297
Last Page : 6313
Authors : Igel P, Geyer R, Strasser A, Dove S, Seifert R, Buschauer A.
Abstract : Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50 = 7.47, alpha = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using membrane preparations of hH(x)R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pKB = 8.42, >300-fold selectivity over the other HR subtypes).
|
Agonist activity at human histamine H3 receptor expressed in Sf9 cells coexpressing Gialpha-2-Gbeta-1-gamma-2 and RGS4 proteins protein by steady-state GTPase assay
|
Homo sapiens
|
25.12
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists.
Year : 2009
Volume : 52
Issue : 20
First Page : 6297
Last Page : 6313
Authors : Igel P, Geyer R, Strasser A, Dove S, Seifert R, Buschauer A.
Abstract : Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50 = 7.47, alpha = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using membrane preparations of hH(x)R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pKB = 8.42, >300-fold selectivity over the other HR subtypes).
|
Agonist activity at human histamine H4 receptor expressed in Sf9 cells coexpressing RGS19 protein by steady-state GTPase assay
|
Homo sapiens
|
12.02
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists.
Year : 2009
Volume : 52
Issue : 20
First Page : 6297
Last Page : 6313
Authors : Igel P, Geyer R, Strasser A, Dove S, Seifert R, Buschauer A.
Abstract : Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50 = 7.47, alpha = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using membrane preparations of hH(x)R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pKB = 8.42, >300-fold selectivity over the other HR subtypes).
|
Activity at human recombinant histamine H1 receptor expressed in Sf9 cells coexpressing RGS4 by steady-state GTPase activity assay
|
Homo sapiens
|
190.55
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chiral NG-acylated hetarylpropylguanidine-type histamine H2 receptor agonists do not show significant stereoselectivity.
Year : 2010
Volume : 20
Issue : 10
First Page : 3173
Last Page : 3176
Authors : Ghorai P, Kraus A, Birnkammer T, Geyer R, Bernhardt G, Dove S, Seifert R, Elz S, Buschauer A.
Abstract : A set of chiral imidazolylpropylguanidines and 2-aminothiazolylpropylguanidines bearing N(G)-3-phenyl- or N(G)-3-cyclohexylbutanoyl residues was synthesized and investigated for histamine H(2) receptor (H(2)R) agonism (guinea pig (gp) right atrium, GTPase assay on recombinant gp and human (h)H(2)R) and for hH(2)R selectivity compared to hH(1)R, hH(3)R and hH(4)R. In contrast to previous studies on arpromidine derivatives, the present investigation of acylguanidine-type compounds revealed only very low eudismic ratios (1.1-3.2), indicating the stereochemistry of the acyl moiety to play only a minor role in this series of H(2)R agonists.
|
Activity at human recombinant histamine H3 receptor expressed in Sf9 cells coexpressing Galphai, Gbeta1gamma2 and RGS4 by steady-state GTPase activity assay
|
Homo sapiens
|
12.88
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chiral NG-acylated hetarylpropylguanidine-type histamine H2 receptor agonists do not show significant stereoselectivity.
Year : 2010
Volume : 20
Issue : 10
First Page : 3173
Last Page : 3176
Authors : Ghorai P, Kraus A, Birnkammer T, Geyer R, Bernhardt G, Dove S, Seifert R, Elz S, Buschauer A.
Abstract : A set of chiral imidazolylpropylguanidines and 2-aminothiazolylpropylguanidines bearing N(G)-3-phenyl- or N(G)-3-cyclohexylbutanoyl residues was synthesized and investigated for histamine H(2) receptor (H(2)R) agonism (guinea pig (gp) right atrium, GTPase assay on recombinant gp and human (h)H(2)R) and for hH(2)R selectivity compared to hH(1)R, hH(3)R and hH(4)R. In contrast to previous studies on arpromidine derivatives, the present investigation of acylguanidine-type compounds revealed only very low eudismic ratios (1.1-3.2), indicating the stereochemistry of the acyl moiety to play only a minor role in this series of H(2)R agonists.
|
Activity at human recombinant GAIP-fused histamine H4 receptor expressed in Sf9 cells coexpressing Galphai, Gbeta1gamma2 by steady-state GTPase activity assay
|
Homo sapiens
|
9.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Chiral NG-acylated hetarylpropylguanidine-type histamine H2 receptor agonists do not show significant stereoselectivity.
Year : 2010
Volume : 20
Issue : 10
First Page : 3173
Last Page : 3176
Authors : Ghorai P, Kraus A, Birnkammer T, Geyer R, Bernhardt G, Dove S, Seifert R, Elz S, Buschauer A.
Abstract : A set of chiral imidazolylpropylguanidines and 2-aminothiazolylpropylguanidines bearing N(G)-3-phenyl- or N(G)-3-cyclohexylbutanoyl residues was synthesized and investigated for histamine H(2) receptor (H(2)R) agonism (guinea pig (gp) right atrium, GTPase assay on recombinant gp and human (h)H(2)R) and for hH(2)R selectivity compared to hH(1)R, hH(3)R and hH(4)R. In contrast to previous studies on arpromidine derivatives, the present investigation of acylguanidine-type compounds revealed only very low eudismic ratios (1.1-3.2), indicating the stereochemistry of the acyl moiety to play only a minor role in this series of H(2)R agonists.
|
Displacement of [3H[N-alpha-methylhistamine form human recombinant histamine H3 receptor expressed in CHO cells after 1 hr by liquid scintillation counting
|
Homo sapiens
|
5.2
nM
|
|
Journal : J. Med. Chem.
Title : Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice.
Year : 2010
Volume : 53
Issue : 9
First Page : 3840
Last Page : 3844
Authors : Ishikawa M, Shinei R, Yokoyama F, Yamauchi M, Oyama M, Okuma K, Nagayama T, Kato K, Kakui N, Sato Y.
Abstract : The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound, 4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain N(tau)-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident-intruder test.
|
Agonist activity at human recombinant histamine H3 receptor expressed in CHO cells assessed as [35S]GTPgammaS binding after 1 hr by liquid scintillation counting
|
Homo sapiens
|
640.0
nM
|
|
Journal : J. Med. Chem.
Title : Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice.
Year : 2010
Volume : 53
Issue : 9
First Page : 3840
Last Page : 3844
Authors : Ishikawa M, Shinei R, Yokoyama F, Yamauchi M, Oyama M, Okuma K, Nagayama T, Kato K, Kakui N, Sato Y.
Abstract : The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound, 4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain N(tau)-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident-intruder test.
|
Displacement of [3H]histamine from human recombinant histamine H4 receptor
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Agonist/antagonist modulation in a series of 2-aryl benzimidazole H4 receptor ligands.
Year : 2010
Volume : 20
Issue : 11
First Page : 3367
Last Page : 3371
Authors : Savall BM, Edwards JP, Venable JD, Buzard DJ, Thurmond R, Hack M, McGovern P.
Abstract : The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.
|
Agonist activity at rat histamine H4 receptor by luciferase reporter gene assay
|
Rattus norvegicus
|
158.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Binding affinity to dog histamine H4 receptor expressed in COS7 cells by radioligand displacement assay
|
Canis lupus familiaris
|
63.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Agonist activity at human recombinant histamine H1 receptor expressed in Sf9 cells coexpressing RGS4 by steady-state GTPase activity assay
|
Homo sapiens
|
199.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Displacement of [3H]-histamine from human histamine H4 receptor expressed in Sf9 cells coexpressing RGS19, Galphai2, Gbeta1gamma2
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Agonist activity at human recombinant histamine H4 receptor expressed in Sf9 cells coexpressing RGS19, Galphai2, Gbeta1gamma2 by steady-state GTPase activity assay
|
Homo sapiens
|
12.59
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Displacement of [3H]Nalpha-methylhistamine from human histamine H3 receptor expressed in human SK-N-MC cells
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Agonist activity at human histamine H3 receptor expressed in human SK-N-MC cells by CRE-beta galactosidase reporter gene assay
|
Homo sapiens
|
5.012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Agonist activity at human histamine H4 receptor expressed in human SK-N-MC cells by CRE-beta galactosidase reporter gene assay
|
Homo sapiens
|
19.95
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Binding affinity to human recombinant histamine H4 receptor expressed in human SK-N-MC cells by radioligand displacement assay
|
Homo sapiens
|
12.59
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Agonist activity at human recombinant histamine H4 receptor expressed in human SK-N-MC cells co-expressing SRE-Luc by luciferase reporter gene assay
|
Homo sapiens
|
79.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Binding affinity to mouse histamine H4 receptor expressed in human SK-N-MC cells by radioligand displacement assay
|
Mus musculus
|
79.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Binding affinity to rat histamine H4 receptor expressed in human SK-N-MC cells by radioligand displacement assay
|
Rattus norvegicus
|
63.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Histamine H4 receptor agonists.
Year : 2010
Volume : 20
Issue : 24
First Page : 7191
Last Page : 7199
Authors : Igel P, Dove S, Buschauer A.
Abstract : Since its discovery 10 years ago the histamine H(4) receptor (H(4)R) has attracted attention as a potential drug target, for instance, for the treatment of inflammatory and allergic diseases. Potent and selective ligands including agonists are required as pharmacological tools to study the role of the H(4)R in vitro and in vivo. Many H(4)R agonists, which were identified among already known histamine receptor ligands, show only low or insufficient H(4)R selectivity. In addition, the investigation of numerous H(4)R agonists in animal models is hampered by species-dependent discrepancies regarding potencies and histamine receptor selectivities of the available compounds, especially when comparing human and rodent receptors. This article gives an overview about structures, potencies, and selectivities of various compounds showing H(4)R agonistic activity and summarizes the structure-activity relationships of selected compound classes.
|
Antiplasmodial activity against Plasmodium falciparum 3D7 infected in RBCs by firefly luciferase reporter gene assay
|
Plasmodium falciparum
|
660.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Discovery of potent small-molecule inhibitors of multidrug-resistant Plasmodium falciparum using a novel miniaturized high-throughput luciferase-based assay.
Year : 2010
Volume : 54
Issue : 9
First Page : 3597
Last Page : 3604
Authors : Lucumi E, Darling C, Jo H, Napper AD, Chandramohanadas R, Fisher N, Shone AE, Jing H, Ward SA, Biagini GA, DeGrado WF, Diamond SL, Greenbaum DC.
Abstract : Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by Plasmodium falciparum. Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites, which necessitates the discovery of new drugs. To identify new antimalarials, we developed an automated 384-well plate screening assay using P. falciparum parasites that stably express cytoplasmic firefly luciferase. After initial optimization, we tested two different types of compound libraries: known bioactive collections (Library of Pharmacologically Active Compounds [LOPAC] and the library from the National Institute of Neurological Disorders and Stroke [NINDS]) and a library of uncharacterized compounds (ChemBridge). A total of 12,320 compounds were screened at 5.5 microM. Selecting only compounds that reduced parasite growth by 85% resulted in 33 hits from the combined bioactive collection and 130 hits from the ChemBridge library. Fifteen novel drug-like compounds from the bioactive collection were found to be active against P. falciparum. Twelve new chemical scaffolds were found from the ChemBridge hits, the most potent of which was a series based on the 1,4-naphthoquinone scaffold, which is structurally similar to the FDA-approved antimalarial atovaquone. However, in contrast to atovaquone, which acts to inhibit the bc(1) complex and block the electron transport chain in parasite mitochondria, we have determined that our new 1,4-napthoquinones act in a novel, non-bc(1)-dependent mechanism and remain potent against atovaquone- and chloroquine-resistant parasites. Ultimately, this study may provide new probes to understand the molecular details of the malaria life cycle and to identify new antimalarials.
|
Displacement of [3H]N-alpha-methylhistamine from human histamine H3 receptor expressed in HEK293 cells after 60 mins by liquid scintillation counting
|
Homo sapiens
|
11.75
nM
|
|
Journal : J. Med. Chem.
Title : Triazole ligands reveal distinct molecular features that induce histamine H4 receptor affinity and subtly govern H4/H3 subtype selectivity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1693
Last Page : 1703
Authors : Wijtmans M, de Graaf C, de Kloe G, Istyastono EP, Smit J, Lim H, Boonnak R, Nijmeijer S, Smits RA, Jongejan A, Zuiderveld O, de Esch IJ, Leurs R.
Abstract : The histamine H(3) (H(3)R) and H(4) (H(4)R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H(4)R/H(3)R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H(4)R affinities and >10-fold H(4)R/H(3)R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H(4)R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H(3)R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H(4)R over H(3)R selectivity.
|
Displacement of [3H]histamine from human histamine H4 receptor expressed in HEK293 cells after 60 mins by liquid scintillation counting
|
Homo sapiens
|
12.02
nM
|
|
Journal : J. Med. Chem.
Title : Triazole ligands reveal distinct molecular features that induce histamine H4 receptor affinity and subtly govern H4/H3 subtype selectivity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1693
Last Page : 1703
Authors : Wijtmans M, de Graaf C, de Kloe G, Istyastono EP, Smit J, Lim H, Boonnak R, Nijmeijer S, Smits RA, Jongejan A, Zuiderveld O, de Esch IJ, Leurs R.
Abstract : The histamine H(3) (H(3)R) and H(4) (H(4)R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H(4)R/H(3)R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H(4)R affinities and >10-fold H(4)R/H(3)R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H(4)R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H(3)R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H(4)R over H(3)R selectivity.
|
Agonist activity at human histamine H4 receptor expressed in HEK293 cells assessed by forskolin induced cAMP response element activation by luciferase reporter gene assay
|
Homo sapiens
|
25.12
nM
|
|
Journal : J. Med. Chem.
Title : Triazole ligands reveal distinct molecular features that induce histamine H4 receptor affinity and subtly govern H4/H3 subtype selectivity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1693
Last Page : 1703
Authors : Wijtmans M, de Graaf C, de Kloe G, Istyastono EP, Smit J, Lim H, Boonnak R, Nijmeijer S, Smits RA, Jongejan A, Zuiderveld O, de Esch IJ, Leurs R.
Abstract : The histamine H(3) (H(3)R) and H(4) (H(4)R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H(4)R/H(3)R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H(4)R affinities and >10-fold H(4)R/H(3)R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H(4)R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H(3)R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H(4)R over H(3)R selectivity.
|
Agonist activity at human histamine H3 receptor expressed in HEK293 cells assessed by forskolin induced cAMP response element activation by luciferase reporter gene assay
|
Homo sapiens
|
15.85
nM
|
|
Journal : J. Med. Chem.
Title : Triazole ligands reveal distinct molecular features that induce histamine H4 receptor affinity and subtly govern H4/H3 subtype selectivity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1693
Last Page : 1703
Authors : Wijtmans M, de Graaf C, de Kloe G, Istyastono EP, Smit J, Lim H, Boonnak R, Nijmeijer S, Smits RA, Jongejan A, Zuiderveld O, de Esch IJ, Leurs R.
Abstract : The histamine H(3) (H(3)R) and H(4) (H(4)R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H(4)R/H(3)R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H(4)R affinities and >10-fold H(4)R/H(3)R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H(4)R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H(3)R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H(4)R over H(3)R selectivity.
|
Displacement of [3H]histamine from human H3 receptor expressed in HEK293 cells after 1 to 1.5 hrs by scintillation counting
|
Homo sapiens
|
6.31
nM
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.
Year : 2011
Volume : 54
Issue : 23
First Page : 8136
Last Page : 8147
Authors : Istyastono EP, Nijmeijer S, Lim HD, van de Stolpe A, Roumen L, Kooistra AJ, Vischer HF, de Esch IJ, Leurs R, de Graaf C.
Abstract : The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.
|
Displacement of [3H]histamine from human H4 receptor expressed in HEK293 cells after 1 to 1.5 hrs by scintillation counting
|
Homo sapiens
|
15.85
nM
|
|
Journal : J. Med. Chem.
Title : Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.
Year : 2011
Volume : 54
Issue : 23
First Page : 8136
Last Page : 8147
Authors : Istyastono EP, Nijmeijer S, Lim HD, van de Stolpe A, Roumen L, Kooistra AJ, Vischer HF, de Esch IJ, Leurs R, de Graaf C.
Abstract : The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.
|
Displacement of [3H]histamine from human H4 receptor expressed in HEK cell membranes
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ligand based design of novel histamine H₄ receptor antagonists; fragment optimization and analysis of binding kinetics.
Year : 2012
Volume : 22
Issue : 1
First Page : 461
Last Page : 467
Authors : Smits RA, Lim HD, van der Meer T, Kuhne S, Bessembinder K, Zuiderveld OP, Wijtmans M, de Esch IJ, Leurs R.
Abstract : The histamine H(4) receptor is a G protein-coupled receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H(4)R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H(4)R antagonist. Analysis of its binding kinetics at the human H(4)R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.
|
Displacement of [3H]histamine from wild type human histamine H4 receptor transfected in HEK293T cells after 1 hr by liquid scintillation counting analysis
|
Homo sapiens
|
19.95
nM
|
|
Journal : MedChemComm
Title : Mapping histamine H4receptorligand binding modes
Year : 2013
Volume : 4
Issue : 1
First Page : 193
Last Page : 204
Authors : Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJP, Haaksma EEJ, Leurs R, de Graaf C
|
Agonist activity at human recombinant histamine H4 receptor-RGS19 fusion protein expressed in Sf9 cells coexpressing Galphai2,Gbeta1gamma2 assessed as [35S]GTPgammaS binding after 90 mins by liquid scintillation counting
|
Homo sapiens
|
20.42
nM
|
|
Journal : MedChemComm
Title : Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approach
Year : 2014
Volume : 5
Issue : 1
First Page : 72
Last Page : 81
Authors : Geyer R, Igel P, Kaske M, Elz S, Buschauer A
|
Agonist activity at human recombinant histamine H3 receptor expressed in Sf9 cells coexpressing Galphai2,Gbeta1gamma2 and RGS4 assessed as [35S]GTPgammaS binding after 90 mins by liquid scintillation counting
|
Homo sapiens
|
12.88
nM
|
|
Journal : MedChemComm
Title : Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approach
Year : 2014
Volume : 5
Issue : 1
First Page : 72
Last Page : 81
Authors : Geyer R, Igel P, Kaske M, Elz S, Buschauer A
|
Agonist activity at human recombinant histamine H4 receptor-RGS19 fusion protein expressed in Sf9 cells coexpressing Galphai2,Gbeta1gamma2 preincubated for 2 mins before [gamma32P]GTP addition measured after 20 mins by steady-state GTPase activity assay
|
Homo sapiens
|
12.02
nM
|
|
Journal : MedChemComm
Title : Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approach
Year : 2014
Volume : 5
Issue : 1
First Page : 72
Last Page : 81
Authors : Geyer R, Igel P, Kaske M, Elz S, Buschauer A
|
Agonist activity at human recombinant histamine H3 receptor expressed in Sf9 cells coexpressing Galphai2,Gbeta1gamma2 and RGS4 preincubated for 2 mins before [gamma32P]GTP addition measured after 20 mins by steady-state GTPase activity assay
|
Homo sapiens
|
25.12
nM
|
|
Journal : MedChemComm
Title : Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approach
Year : 2014
Volume : 5
Issue : 1
First Page : 72
Last Page : 81
Authors : Geyer R, Igel P, Kaske M, Elz S, Buschauer A
|
Agonist activity at human recombinant histamine H1 receptor expressed in Sf9 cells coexpressing RGS4 preincubated for 2 mins before [gamma32P]GTP addition measured after 20 mins by steady-state GTPase activity assay
|
Homo sapiens
|
190.55
nM
|
|
Journal : MedChemComm
Title : Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl-guanidines at the four histamine receptor subtypes: a bioisosteric approach
Year : 2014
Volume : 5
Issue : 1
First Page : 72
Last Page : 81
Authors : Geyer R, Igel P, Kaske M, Elz S, Buschauer A
|
Binding affinity to histamine H4 receptor (unknown origin)
|
Homo sapiens
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
Year : 2015
Volume : 58
Issue : 18
First Page : 7119
Last Page : 7127
Authors : Tichenor MS, Thurmond RL, Venable JD, Savall BM.
Abstract : Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
|
Binding affinity to histamine H3 receptor (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
Year : 2015
Volume : 58
Issue : 18
First Page : 7119
Last Page : 7127
Authors : Tichenor MS, Thurmond RL, Venable JD, Savall BM.
Abstract : Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
|
Binding affinity to human histamine H4 receptor
|
Homo sapiens
|
4.8
nM
|
|
Journal : J. Med. Chem.
Title : Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
Year : 2015
Volume : 58
Issue : 18
First Page : 7119
Last Page : 7127
Authors : Tichenor MS, Thurmond RL, Venable JD, Savall BM.
Abstract : Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
|
Binding affinity to guinea pig histamine H4 receptor
|
Cavia porcellus
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
Year : 2015
Volume : 58
Issue : 18
First Page : 7119
Last Page : 7127
Authors : Tichenor MS, Thurmond RL, Venable JD, Savall BM.
Abstract : Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
|
Binding affinity to mouse histamine H4 receptor
|
Mus musculus
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
Year : 2015
Volume : 58
Issue : 18
First Page : 7119
Last Page : 7127
Authors : Tichenor MS, Thurmond RL, Venable JD, Savall BM.
Abstract : Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
|
Binding affinity to rat histamine H4 receptor
|
Rattus norvegicus
|
136.0
nM
|
|
Journal : J. Med. Chem.
Title : Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
Year : 2015
Volume : 58
Issue : 18
First Page : 7119
Last Page : 7127
Authors : Tichenor MS, Thurmond RL, Venable JD, Savall BM.
Abstract : Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
|
Displacement of [3H]-histamine from human histamine H4 receptor expressed in human SK-N-MC cells after 1 hr
|
Homo sapiens
|
15.85
nM
|
|
Journal : MedChemComm
Title : Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4receptor
Year : 2015
Volume : 6
Issue : 6
First Page : 1003
Last Page : 1017
Authors : Istyastono EP, Kooistra AJ, Vischer HF, Kuijer M, Roumen L, Nijmeijer S, Smits RA, de Esch IJP, Leurs R, de Graaf C
|
Antagonist activity at human histamine 4 receptor expressed in Sf9 cell membranes co-expressing Galphai2 and Gbeta1gamma2 assessed as [35S]GTPgammaS binding by scintillation counting
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2,4-Diaminopyrimidines as dual ligands at the histamine H1 and H4 receptor-H1/H4-receptor selectivity.
Year : 2016
Volume : 26
Issue : 2
First Page : 292
Last Page : 300
Authors : Hammer SG, Gobleder S, Naporra F, Wittmann HJ, Elz S, Heinrich MR, Strasser A.
Abstract : Distinct diaminopyrimidines, for example, 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine are histamine H4 receptor (H4R) antagonists and show high affinity to the H4R, but only a moderate affinity to the histamine H1 receptor (H1R). Within previous studies it was shown that an aromatic side chain with a distinct distance to the basic amine and aromatic core is necessary for affinity to the human H1R (hH1R). Thus, a rigid aminopyrimidine with a tricyclic core was used as a lead structure. There, (1) the flexible aromatic side chain was introduced, (2) the substitution pattern of the pyrimidine core was exchanged and (3) rigidity was decreased by opening the tricyclic core. Within the present study, two compounds with similar affinity in the one digit μM range to the human H1R and H4R were identified. While the affinity at the hH1R increased about 4- to 8-fold compared to the parent diaminopyrimidine, the affinity to the hH4R decreased about 5- to 8-fold. In addition to the parent diaminopyrimidine, two selected compounds were docked into the H1R and H4R and molecular dynamic studies were performed to predict the binding mode and explain the experimental results on a molecular level. The two new compounds may be good lead structures for the development of dual H1/H4 receptor ligands with affinities in the same range.
|
Agonist activity at human histamine H3 receptor expressed in sf9 cell membrane co-expressing mammalian Galphai2 and Gbeta1gamma2 incubated for 90 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.
Year : 2016
Volume : 59
Issue : 7
First Page : 3452
Last Page : 3470
Authors : Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A.
Abstract : 2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
|
Agonist activity at human histamine H4 receptor expressed in sf9 cell membrane co-expressing mammalian Galphai2 and Gbeta1gamma2 incubated for 90 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.
Year : 2016
Volume : 59
Issue : 7
First Page : 3452
Last Page : 3470
Authors : Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A.
Abstract : 2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
|
Agonist activity at human histamine H1 receptor expressed in sf9 cell membrane co-expressing RGS4 or RGS9 assessed as increase in 32Pi level incubated for 20 mins by liquid scintillation counting in presence of [gamma32P]GTP
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.
Year : 2016
Volume : 59
Issue : 7
First Page : 3452
Last Page : 3470
Authors : Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A.
Abstract : 2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
|
Agonist activity at human SF-His6-tagged histamine H4 receptor expressed in HEK293 cells assessed as inhibition of forskolin-stimulated response incubated for 5 hrs by luciferase reporter gene assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.
Year : 2016
Volume : 59
Issue : 7
First Page : 3452
Last Page : 3470
Authors : Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A.
Abstract : 2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
|
Agonist activity at mouse SF-His6-tagged histamine H4 receptor expressed in HEK293 cells assessed as inhibition of forskolin-stimulated response incubated for 5 hrs by luciferase reporter gene assay
|
Mus musculus
|
94.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.
Year : 2016
Volume : 59
Issue : 7
First Page : 3452
Last Page : 3470
Authors : Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A.
Abstract : 2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
|
Binding affinity to histamine H4 receptor (unknown origin)
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and evaluation of a 2-benzothiazolylphenylmethyl ether class of histamine H4 receptor antagonists.
Year : 2016
Volume : 26
Issue : 21
First Page : 5263
Last Page : 5266
Authors : Labeeuw O, Levoin N, Billot X, Danvy D, Calmels T, Krief S, Ligneau X, Berrebi-Bertrand I, Robert P, Lecomte JM, Schwartz JC, Capet M.
Abstract : Synthesis and biological evaluation of a new class of histamine H4 receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.
|
Binding affinity to histamine H3 receptor (unknown origin)
|
Homo sapiens
|
12.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and evaluation of a 2-benzothiazolylphenylmethyl ether class of histamine H4 receptor antagonists.
Year : 2016
Volume : 26
Issue : 21
First Page : 5263
Last Page : 5266
Authors : Labeeuw O, Levoin N, Billot X, Danvy D, Calmels T, Krief S, Ligneau X, Berrebi-Bertrand I, Robert P, Lecomte JM, Schwartz JC, Capet M.
Abstract : Synthesis and biological evaluation of a new class of histamine H4 receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.
|
Binding affinity to human H4R
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Binding affinity to mouse H4R
|
Mus musculus
|
42.0
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Binding affinity to rat H4R
|
Rattus norvegicus
|
134.0
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Agonist activity at human H4R by [35S]-GTPgammaS-binding assay
|
Homo sapiens
|
7.413
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Agonist activity at human H4R expressed in HEK293-SF-hH4R-His6-CRE-Luc cells incubated for 5 hrs by luciferase reporter gene assay
|
Homo sapiens
|
16.98
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Agonist activity at human H4R expressed in HEK293T-beta-arr2-hH4R cells by beta-arrestin2 recruitment assay
|
Homo sapiens
|
33.88
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Agonist activity at mouse H4R expressed in HEK293-SF-mH4R-His6-CRE-Luc cells incubated for 5 hrs by luciferase reporter gene assay
|
Mus musculus
|
87.1
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Agonist activity at rat H4R expressed in HEK293-SF-rH4R-His6-CRE-Luc cells incubated for 5 hrs by luciferase reporter gene assay
|
Rattus norvegicus
|
295.12
nM
|
|
Journal : J Med Chem
Title : [<sup>3</sup>H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H<sub>4</sub> Receptors.
Year : 2019
Volume : 62
Issue : 17
First Page : 8338
Last Page : 8356
Authors : Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G.
Abstract : Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H<sub>4</sub> receptors (H<sub>4</sub>R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH<sub>4</sub>Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH<sub>4</sub>Rs: UR-DEBa148 (<i>N</i>-neopentyl-4-(1,4,6,7-tetrahydro-5<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>43</b>), the most potent [pEC<sub>50</sub> (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(<i>R</i>)-4-[3-(dimethylamino)pyrrolidin-1-yl]-<i>N</i>-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), <b>46</b>, pEC<sub>50</sub> (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H<sub>4</sub>R ligand. After radiolabeling, binding studies with [<sup>3</sup>H]UR-DEBa176 ([<sup>3</sup>H]<b>46</b>) at the h/m/rH<sub>4</sub>Rs revealed comparable <i>K</i><sub>d</sub> values (41/17/22 nM), low nonspecific binding (11-17%, ∼<i>K</i><sub>d</sub>), and fast associations/dissociations (25-30 min) and disclosed [<sup>3</sup>H]UR-DEBa176 as useful molecular tool to determine h/m/rH<sub>4</sub>R binding affinities for H<sub>4</sub>R ligands.
|
Displacement of [3H]NAMH from human H3R expressed in HEK293T cells incubated for 2 hrs by microbeta scintillation counting analysis
|
Homo sapiens
|
12.59
nM
|
|
Journal : J Med Chem
Title : 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity.
Year : 2019
Volume : 62
Issue : 23
First Page : 10848
Last Page : 10866
Authors : Wágner G, Mocking TAM, Arimont M, Provensi G, Rani B, Silva-Marques B, Latacz G, Da Costa Pereira D, Karatzidou C, Vischer HF, Wijtmans M, Kieć-Kononowicz K, de Esch IJP, Leurs R.
Abstract : Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.
|
Agonist activity at human H3R expressed on HEK293T cells assessed as inhibition of forskolin-induced CRE-driven luciferase activity co-incubated with forskolin for 6 hrs and measured after 30 mins by CRE-luciferase reporter gene assay
|
Homo sapiens
|
2.512
nM
|
|
Journal : J Med Chem
Title : 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity.
Year : 2019
Volume : 62
Issue : 23
First Page : 10848
Last Page : 10866
Authors : Wágner G, Mocking TAM, Arimont M, Provensi G, Rani B, Silva-Marques B, Latacz G, Da Costa Pereira D, Karatzidou C, Vischer HF, Wijtmans M, Kieć-Kononowicz K, de Esch IJP, Leurs R.
Abstract : Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.
|
Agonist activity at human H3R expressed on HEK293T cells by [35S]GTPgammaS binding assay
|
Homo sapiens
|
63.1
nM
|
|
Journal : J Med Chem
Title : 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity.
Year : 2019
Volume : 62
Issue : 23
First Page : 10848
Last Page : 10866
Authors : Wágner G, Mocking TAM, Arimont M, Provensi G, Rani B, Silva-Marques B, Latacz G, Da Costa Pereira D, Karatzidou C, Vischer HF, Wijtmans M, Kieć-Kononowicz K, de Esch IJP, Leurs R.
Abstract : Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.
|
Displacement of [3H]-N-alpha-methylhistamine from human histamine H3 receptor expressed in SK-N-MC cells incubated for 40 min by liquid scintillation counting analysis
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity.
Year : 2019
Volume : 62
Issue : 23
First Page : 10848
Last Page : 10866
Authors : Wágner G, Mocking TAM, Arimont M, Provensi G, Rani B, Silva-Marques B, Latacz G, Da Costa Pereira D, Karatzidou C, Vischer HF, Wijtmans M, Kieć-Kononowicz K, de Esch IJP, Leurs R.
Abstract : Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.
|
Agonist activity at human H3R expressed on SK-N-MC cells assessed as inhibition of forskolin-induced beta galactosidase activity preincubated with forskolin for 6 hrs followed compound addition by CRE-luciferase reporter gene assay
|
Homo sapiens
|
5.012
nM
|
|
Journal : J Med Chem
Title : 4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity.
Year : 2019
Volume : 62
Issue : 23
First Page : 10848
Last Page : 10866
Authors : Wágner G, Mocking TAM, Arimont M, Provensi G, Rani B, Silva-Marques B, Latacz G, Da Costa Pereira D, Karatzidou C, Vischer HF, Wijtmans M, Kieć-Kononowicz K, de Esch IJP, Leurs R.
Abstract : Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure-activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
19.79
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.67
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.3
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.3
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Displacement of [3H]UR-DE257 from Gsalphas-coupled human H2R expressed in baculovirus infected Sf9 cells incubated for 60 mins by scintillation counting method
|
Homo sapiens
|
295.12
nM
|
|
Journal : ACS Med Chem Lett
Title : Fluorescent H<sub>2</sub> Receptor Squaramide-Type Antagonists: Synthesis, Characterization, and Applications.
Year : 2020
Volume : 11
Issue : 8
First Page : 1521
Last Page : 1528
Authors : Biselli S, Alencastre I, Tropmann K, Erdmann D, Chen M, Littmann T, Maia AF, Gomez-Lazaro M, Tanaka M, Ozawa T, Keller M, Lamghari M, Buschauer A, Bernhardt G.
Abstract : Fluorescence labeled ligands have been gaining importance as molecular tools, enabling receptor-ligand-binding studies by various fluorescence-based techniques. Aiming at red-emitting fluorescent ligands for the hH<sub>2</sub>R, a series of squaramides labeled with pyridinium or cyanine fluorophores (<b>19</b>-<b>27</b>) was synthesized and characterized. The highest hH<sub>2</sub>R affinities in radioligand competition binding assays were obtained in the case of pyridinium labeled antagonists <b>19</b>-<b>21</b> (p<i>K</i> <sub>i</sub>: 7.71-7.76) and cyanine labeled antagonists <b>23</b> and <b>25</b> (p<i>K</i> <sub>i</sub>: 7.67, 7.11). These fluorescent ligands proved to be useful tools for binding studies (saturation and competition binding as well as kinetic experiments), using confocal microscopy, flow cytometry, and high content imaging. Saturation binding experiments revealed p<i>K</i> <sub>d</sub> values comparable to the p<i>K</i> <sub>i</sub> values. The fluorescent probes <b>21</b>, <b>23</b>, and <b>25</b> could be used to localize H<sub>2</sub> receptors in HEK cells and to determine the binding affinities of unlabeled compounds.
|
Agonist activity at human H3 receptor stably transfected in CHO-DUKX cells assessed as increase in cAMP accumulation by measuring reduction in forskolin level by HitHunter-cAMP assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel pyrrolidinone derivative lacks claimed histamine H receptor stimulation in receptor binding and functional studies.
Year : 2020
Volume : 191
First Page : 112150
Last Page : 112150
Authors : Reiner D,Zivkovic A,Labeeuw O,Krief S,Capet M,Stark H
Abstract : Since the discovery and early characterization of the histamine H receptor (HR) in the 1980's, predominantly imidazole-based agonists were presented to the scientific community such as N-methylhistamine (N-MeHA) or (R)-α-methylhistamine ((R)α-MeHA). Whereas therapeutic applications have been prompted for HR agonists such as treatment of pain, asthma and obesity, several drawbacks associated with imidazole-containing ligands makes the search for new agonists for this receptor demanding. Accordingly, high interest arose after publication of several pyrrolidindione-based, highly affine HR agonists within this journal that avoid the imidazole moiety and thus, presenting a novel type of potential pharmacophores (Ghoshal, Anirban et al., 2018). In our present study performed in two independent laboratories, we further evaluated the exposed lead-compound (EC = 0.1 nM) of the previous research project with regards to pharmacological behavior at HR. Thereby, no binding affinity was observed in neither [H]N-MeHA nor bodilisant displacement assays that contradicts the previously published activity. Additional functional exploration employing GTPγ[S], cAMP-accumulation assay and cAMP response element (CRE)-driven reporter gene assays exhibited slight partial agonist properties of such pyrrolidindiones but acting apart from the reported concentration range. We conclude, that the previously reported actions of such pyrrolidindiones result from an overestimation based on the method of measurement and thus, we cast doubt on the new pharmacophores with HR agonist activity.
|
Agonist activity at human H3 receptor expressed in CHO cells assessed as increase in cAMP accumulation by measuring reduction in forskolin level incubated for 4 hrs by CRE/MRE-luciferase reporter gene assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel pyrrolidinone derivative lacks claimed histamine H receptor stimulation in receptor binding and functional studies.
Year : 2020
Volume : 191
First Page : 112150
Last Page : 112150
Authors : Reiner D,Zivkovic A,Labeeuw O,Krief S,Capet M,Stark H
Abstract : Since the discovery and early characterization of the histamine H receptor (HR) in the 1980's, predominantly imidazole-based agonists were presented to the scientific community such as N-methylhistamine (N-MeHA) or (R)-α-methylhistamine ((R)α-MeHA). Whereas therapeutic applications have been prompted for HR agonists such as treatment of pain, asthma and obesity, several drawbacks associated with imidazole-containing ligands makes the search for new agonists for this receptor demanding. Accordingly, high interest arose after publication of several pyrrolidindione-based, highly affine HR agonists within this journal that avoid the imidazole moiety and thus, presenting a novel type of potential pharmacophores (Ghoshal, Anirban et al., 2018). In our present study performed in two independent laboratories, we further evaluated the exposed lead-compound (EC = 0.1 nM) of the previous research project with regards to pharmacological behavior at HR. Thereby, no binding affinity was observed in neither [H]N-MeHA nor bodilisant displacement assays that contradicts the previously published activity. Additional functional exploration employing GTPγ[S], cAMP-accumulation assay and cAMP response element (CRE)-driven reporter gene assays exhibited slight partial agonist properties of such pyrrolidindiones but acting apart from the reported concentration range. We conclude, that the previously reported actions of such pyrrolidindiones result from an overestimation based on the method of measurement and thus, we cast doubt on the new pharmacophores with HR agonist activity.
|
Displacement of [3H]-Histamine from human histamine 4 receptor transfected in HEK293T cells incubated for 16 hrs by liquid scintillation counter analysis
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg Med Chem
Title : Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H and H receptors.
Year : 2021
Volume : 30
First Page : 115924
Last Page : 115924
Authors : Corrêa MF,Balico-Silva AL,Kiss DJ,Fernandes GAB,Maraschin JC,Parreiras-E-Silva LT,Varela MT,Simões SC,Bouvier M,Keserű GM,Costa-Neto CM,Fernandes JPS
Abstract : Histamine acts through four different receptors (HR-HR), the HR and HR being the most explored in the last years as drug targets. The HR is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while HR blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human HR/HR ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hHR affinity (pK > 7), compound 1h being the most potent (pK 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gα activity indicated that the compounds are potent antagonists. Only one compound (2c, pK 7.1) presented high affinity for hHR. In contrast to what was observed for hHR, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hHR, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hHR. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hHR was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hHR and hHR.
|
Displacement of [3H]-Histamine from human histamine 3 receptor transfected in HEK293T cells incubated for 16 hrs by liquid scintillation counter analysis
|
Homo sapiens
|
2.512
nM
|
|
Journal : Bioorg Med Chem
Title : Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H and H receptors.
Year : 2021
Volume : 30
First Page : 115924
Last Page : 115924
Authors : Corrêa MF,Balico-Silva AL,Kiss DJ,Fernandes GAB,Maraschin JC,Parreiras-E-Silva LT,Varela MT,Simões SC,Bouvier M,Keserű GM,Costa-Neto CM,Fernandes JPS
Abstract : Histamine acts through four different receptors (HR-HR), the HR and HR being the most explored in the last years as drug targets. The HR is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while HR blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human HR/HR ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hHR affinity (pK > 7), compound 1h being the most potent (pK 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gα activity indicated that the compounds are potent antagonists. Only one compound (2c, pK 7.1) presented high affinity for hHR. In contrast to what was observed for hHR, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hHR, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hHR. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hHR was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hHR and hHR.
|
Displacement of [3H]UR-DE257 from human histamine H2 receptor expressed in sf9 insect cell membranes co-expressing GSalphaS incubated for 60 mins by microbeta scintillation counting method
|
Homo sapiens
|
263.03
nM
|
|
|
Displacement of [3H]UR-P129 from human histamine H3 receptor expressed in sf9 insect cell membranes co-expressing Galphai2/Gbeta1gamma2 incubated for 60 mins by microbeta scintillation counting method
|
Homo sapiens
|
25.7
nM
|
|
|
Displacement of [3H]histamine from human histamine H4 receptor expressed in sf9 insect cell membranes co-expressing Galphai2/Gbeta1gamma2 incubated for 60 mins by microbeta scintillation counting method
|
Homo sapiens
|
25.12
nM
|
|
|
Agonist activity at guinea pig right atrium histamine H2 receptor assessed as increase in heart rate incubated for 30 mins in presence of cimetidine
|
Cavia porcellus
|
691.83
nM
|
|
|
Agonist activity at human histamine receptor expressed in sf9 insect cell membranes co-exprssing GsalphaS incubated for 90 mins [35S]GTPgammaS binding based microbeta scintillation counting analysis
|
Homo sapiens
|
977.24
nM
|
|
|
Binding affinity in Nluc-hH3R assessed in HEK293 cells by NanoBRET binding assay
|
Homo sapiens
|
588.84
nM
|
|
|
Binding affinity in Nluc-hH3R assessed in HEK293T cells by NanoBRET binding assay
|
Homo sapiens
|
501.19
nM
|
|
|
Agonist activity at human H2 receptor expressed in HEK293T-ARRB2 cells assessed as stimulation of beta-arrestin 2 recruitment
|
Homo sapiens
|
114.82
nM
|
|
|
Displacement of [3H]UR-DE257 from Gsalphas-coupled human H2R expressed in Sf9 cell membranes by competitive binding assay
|
Homo sapiens
|
263.03
nM
|
|
