|
Binding affinity against 5-hydroxytryptamine 3 receptor using [3H]BRL-43694 in rat posterior cortex
|
Rattus norvegicus
|
443.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of a potent 5-HT4 receptor agonist with nanomolar affinity
Year : 1994
Volume : 4
Issue : 12
First Page : 1433
Last Page : 1436
Authors : Langlois M, Zhang L, Bre mont B, Shen S, Manara L, Croci T
|
Binding affinity against 5-hydroxytryptamine 3 receptor using [3H]BRL-43694 as radioligand in rat posterior cortex
|
None
|
443.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological activity of a macrocyclic benzamide
Year : 1995
Volume : 5
Issue : 8
First Page : 795
Last Page : 798
Authors : Langlois M, Yang D, Bremont B, Shen S
|
Displacement of the 5-hydroxytryptamine 3 receptor ligand [3H]GR-65630 from rat brain cortical membranes.
|
None
|
995.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides.
Year : 1992
Volume : 35
Issue : 5
First Page : 895
Last Page : 903
Authors : Youssefyeh RD, Campbell HF, Klein S, Airey JE, Darkes P, Powers M, Schnapper M, Neuenschwander K, Fitzpatrick LR, Pendley CE.
Abstract : This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.
|
Binding affinity at 5-hydroxytryptamine 3 receptor in rat entorhinal cortex by [3H]BRL-43694 displacement.
|
None
|
490.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Serotoninergic 5-HT3 and 5-HT4 receptor activities of dihydrobenzofuran carboxylic acid derivatives
Year : 1996
Volume : 6
Issue : 3
First Page : 263
Last Page : 266
Authors : Fancelli D, Caccia C, Fornaretto M, McArthur R, Severino D, Vaghi F, Varasi M
|
Compound was evaluated for its binding affinity for 5-hydroxytryptamine 3 receptor by measuring displacement [3H]GR-65630 in rat cerebral cortex
|
None
|
348.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-HT3 antagonists derived from aminopyridazine-type muscarinic M1 agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 311
Last Page : 317
Authors : Rival Y, Hoffmann R, Didier B, Rybaltchenko V, Bourguignon JJ, Wermuth CG.
Abstract : A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 +/- 0.5 A between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 +/- 0.03 A of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC50 values for 5-HT3 receptor binding ([3H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([3H] pirenzepine) layed over 10,000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist-like effects on those responsible for the slowly desensitizing components.
|
Inhibitory activity against 5-hydroxytryptamine 3 receptor in rat cortical membranes using [3H]- 1-Methyl-1H-indazole-3-carboxylic acid (8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide as a radioligand
|
None
|
502.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biochemical evaluation of tritium-labeled 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxa mide, a useful radioligand for 5HT3 receptors.
Year : 1990
Volume : 33
Issue : 12
First Page : 3176
Last Page : 3181
Authors : Robertson DW, Bloomquist W, Cohen ML, Reid LR, Schenck K, Wong DT.
Abstract : The advent of potent, highly selective 5HT3 receptor antagonists has stimulated considerable interest in 5HT3 receptor mediated physiology and pharmacology. To permit detailed biochemical studies regarding interaction of the indazole class of serotonin (5HT) antagonists with 5HT3 receptors in multiple tissues, we synthesized 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole- 3-carboxamide (LY278584, compound 9) in high specific activity, tritium-labeled form. This radioligand was selected as a synthetic target because of its potency as a 5HT3-receptor antagonist, its selectivity for this receptor viz a viz other 5HT-receptor subtypes, and the ability to readily incorporate three tritia via the indazole N-CH3 substituent. Alkylation of N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxamide (8) with sodium hydride and tritium-labeled iodomethane, followed by HPLC purification, resulted in [3H]-9 with a radiochemical purity of 99% and a specific activity of 80.5 Ci/mmol. This radioligand bound with high affinity to a single class of saturable recognition sites in membranes isolated from cerebral cortex of rat brain. The Kd was 0.69 nM and the Bmax was 16.9 fmol/mg of protein. The specific binding was excellent, and accounted for 83-93% of total binding at concentrations of 2 nM or less. The potencies of known 5HT3-receptor antagonists as inhibitors of [3H]-9 binding correlated well with their pharmacological receptor affinities as antagonists of 5HT-induced decreases in heart rate and contraction of guinea pig ileum, suggesting the central recognition site for this radioligand may be extremely similar to or identical with peripheral 5HT3 receptors.
|
Inhibition of [3H]GR-65630 binding to 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : SC-53116: the first selective agonist at the newly identified serotonin 5-HT4 receptor subtype.
Year : 1992
Volume : 35
Issue : 8
First Page : 1486
Last Page : 1489
Authors : Flynn DL, Zabrowski DL, Becker DP, Nosal R, Villamil CI, Gullikson GW, Moummi C, Yang DC.
|
Compound was evaluated for the binding affinity at 5- HT3 receptor subtype
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site.
Year : 1995
Volume : 38
Issue : 13
First Page : 2326
Last Page : 2330
Authors : Buchheit KH, Gamse R, Giger R, Hoyer D, Klein F, Klöppner E, Pfannkuche HJ, Mattes H.
Abstract : The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.
|
Potency at neuronal 5-hydroxytryptamine 3 receptors in the rabbit heart
|
Oryctolagus cuniculus
|
50.12
nM
|
|
Journal : J. Med. Chem.
Title : Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site.
Year : 1990
Volume : 33
Issue : 6
First Page : 1594
Last Page : 1600
Authors : Hibert MF, Hoffmann R, Miller RC, Carr AA.
Abstract : A conformation-activity relationship study of 5-HT3 receptor antagonists was used to define a pharmacophore and receptor map to qualitatively account for their activity. The design and synthesis of specific keto-amino-indole derivatives that are potent 5-HT3 receptor antagonists gave some support to the model.
|
Evaluated for the antagonistic activity against Serotonin 5-hydroxytryptamine 3 receptor in isolated perfused rabbit heart (RH)
|
Oryctolagus cuniculus
|
79.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel ligands for the 5-HT3 and the 5-HT4 receptor
Year : 1992
Volume : 2
Issue : 5
First Page : 461
Last Page : 466
Authors : Blum E, Buchheit K, Buescher H, Gamse R, Kloeppner E, Meigel H, Papageorgiou C, Waelchli R, Revesz L
|
Antagonistic activity against Serotonin 5-hydroxytryptamine 3 receptor in isolated rabbit vagus nerve (RVN)
|
Oryctolagus cuniculus
|
50.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel ligands for the 5-HT3 and the 5-HT4 receptor
Year : 1992
Volume : 2
Issue : 5
First Page : 461
Last Page : 466
Authors : Blum E, Buchheit K, Buescher H, Gamse R, Kloeppner E, Meigel H, Papageorgiou C, Waelchli R, Revesz L
|
Inhibition of [3H]GR-65630 binding to rat cortical membrane 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
880.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamides and their affinities for 5-HT3 and dopamine D2 receptors.
Year : 1998
Volume : 8
Issue : 12
First Page : 1551
Last Page : 1554
Authors : Hirokawa Y, Yoshida N, Kato S.
Abstract : A series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamide derivatives were prepared and evaluated for their binding to 5-HT3 and dopamine D2 receptors. Among them, the 5-bromo-2-methoxy-6-methylaminonicotinamide 16 and its (R)-isomer were found to have potent affinities for both receptors. The affinities of (R)-16 for 5-HT3 and dopamine D2 receptors are approximately 3-fold higher than those of the corresponding benzamide (R)-1 (IC50: 1.1 and 12 nM vs. 2.9 and 35 nM, respectively).
|
Binding affinity against 5-hydroxytryptamine 3 receptor in rat cortical membrane using [3H]GR-65630 as radioligand
|
None
|
880.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel series of N-(hexahydro-1,4-diazepin-6-yl) and N-(hexahydroazepin- 3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors.
Year : 1998
Volume : 8
Issue : 6
First Page : 619
Last Page : 624
Authors : Hirokawa Y, Morie T, Yamazaki H, Yoshida N, Kato S.
Abstract : A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine D2 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.
|
Concentration required to inhibit the binding of radioligand [3H]GR-65630 to serotonin 5-hydroxytryptamine-3 receptor (5-HT 3 receptor)in rat brain cortical membrane
|
None
|
228.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Inhibition of [3H]GR-65630 binding to rat cortical membrane serotonin 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
5-hydroxytryptamine 4 receptor agonist activity, concentration which gave 50% increase in the response to electrically-stimulated myenteric plexus and longitudinal muscle of the guinea pig ileum
|
Cavia porcellus
|
5.7
nM
|
|
Journal : J. Med. Chem.
Title : New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and antagonists for 5-HT4 receptors.
Year : 1997
Volume : 40
Issue : 4
First Page : 608
Last Page : 621
Authors : Yang D, Soulier JL, Sicsic S, Mathé-Allainmat M, Brémont B, Croci T, Cardamone R, Aureggi G, Langlois M.
Abstract : A number of benzoates derived from 4-amino-5-chloro-2-methoxybenzoic acid and substituted 1-piperidineethanol were synthesized and found to be potent 5-HT4 receptor agonists in the electrically-stimulated myenteric plexus and longitudinal muscle of the guinea pig ileum and the rat esophagus muscle. Monosubstitution of the piperidine ring with Me, OH, NH-Ac, or CONH2 groups gave compounds equipotent to 7a (ML 10302), a 5-HT4 receptor agonist previously reported to have nanomolar affinity. 7a,k were as potent as serotonin (5-HT) but had maximal responses which were only 60-80% of that of 5-HT, suggesting a partial agonist profile for these compounds. Binding assays were performed with [3H]GR 113808 in the rat striatum, and several of these compounds were found to have nanomolar affinity for 5-HT4 receptors (7a, Ki = 1.07 +/- 0.5 nM; 7k, Ki = 1.0 +/- 0.3 nM). The introduction of two methyl groups on the piperidine ring brought about a dramatic change in the pharmacological profile of 2-[(cis- and trans-3,5-dimethylpiperidinyl)ethyl]-4-amino-5-chloro-2- methoxybenzoate, 7g,h. 7g (Ki = 0.26 +/- 0.06 nM) inhibited the relaxant action of 5-HT in the rat esophagus muscle with a pA2 value of 8.6. The advantage of the ester function was demonstrated by comparing the activity of several such compounds at 5-HT4 receptors with those of the corresponding amidic derivatives. This difference was less marked when the basic moiety was sterically constrained as in the quinuclidine and tropane moieties. Structural analyses of 7a,g were performed by determining their X-ray crystal structures and by molecular modeling (SYBYL). A relatively limited number of minimum energy conformers was found for both compounds. They were characterized by the cis folded conformation of the ethyl chain and by the orientation of the lone pair of the nitrogen atom pointing out of the molecule as seen in conformationally-constrained benzamides such as zacopride and renzapride. A hypothetical model for the 5-HT4 receptor with two sites for the binding of agonist and antagonist molecules was proposed.
|
Concentration of compound required to inhibit the binding of radioligand [3H]GR-113808 to serotonin 5-hydroxytryptamine 4 receptor in guinea-pig striatum
|
Cavia porcellus
|
912.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Inhibition of [3H]GR-113808 binding to guinea pig striatum 5-hydroxytryptamine 4 receptor
|
Cavia porcellus
|
546.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Tested for its agonist potency against the 5-hydroxytryptamine 4 receptor located in the rat esophageal tunica muscularis mucosae
|
None
|
794.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quaternised renzapride as a potent and selective 5-HT4 receptor agonist
Year : 1993
Volume : 3
Issue : 4
First Page : 633
Last Page : 634
Authors : Baxter G, Boyland P, Gaster L, King F
|
Binding affinity against 5-hydroxytryptamine 4 receptor using [3H]GR-113808 as radioligand in rat striatum
|
Rattus norvegicus
|
975.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of a potent 5-HT4 receptor agonist with nanomolar affinity
Year : 1994
Volume : 4
Issue : 12
First Page : 1433
Last Page : 1436
Authors : Langlois M, Zhang L, Bre mont B, Shen S, Manara L, Croci T
|
Binding affinity against 5-hydroxytryptamine 4 receptor using [3H]GR-113808 as radioligand in rat striatum
|
None
|
974.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological activity of a macrocyclic benzamide
Year : 1995
Volume : 5
Issue : 8
First Page : 795
Last Page : 798
Authors : Langlois M, Yang D, Bremont B, Shen S
|
Binding affinity at 5-hydroxytryptamine 4 receptor in rat striatum by [3H]GR-113808 displacement.
|
None
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Serotoninergic 5-HT3 and 5-HT4 receptor activities of dihydrobenzofuran carboxylic acid derivatives
Year : 1996
Volume : 6
Issue : 3
First Page : 263
Last Page : 266
Authors : Fancelli D, Caccia C, Fornaretto M, McArthur R, Severino D, Vaghi F, Varasi M
|
Binding affinity to 5-hydroxytryptamine 3 receptor using [3H]GR-65630 as radioligand in rat cortex
|
None
|
199.53
nM
|
|
Journal : J. Med. Chem.
Title : Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site.
Year : 1990
Volume : 33
Issue : 6
First Page : 1594
Last Page : 1600
Authors : Hibert MF, Hoffmann R, Miller RC, Carr AA.
Abstract : A conformation-activity relationship study of 5-HT3 receptor antagonists was used to define a pharmacophore and receptor map to qualitatively account for their activity. The design and synthesis of specific keto-amino-indole derivatives that are potent 5-HT3 receptor antagonists gave some support to the model.
|
Binding affinity to 5-hydroxytryptamine 3 receptor using [3H]quipazine as radioligand in rat cortex
|
None
|
229.09
nM
|
|
Journal : J. Med. Chem.
Title : Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site.
Year : 1990
Volume : 33
Issue : 6
First Page : 1594
Last Page : 1600
Authors : Hibert MF, Hoffmann R, Miller RC, Carr AA.
Abstract : A conformation-activity relationship study of 5-HT3 receptor antagonists was used to define a pharmacophore and receptor map to qualitatively account for their activity. The design and synthesis of specific keto-amino-indole derivatives that are potent 5-HT3 receptor antagonists gave some support to the model.
|
Tested for its binding affinity by measuring its ability to displace [3H]granisetron from 5-hydroxytryptamine 3 receptor in rat cortex
|
None
|
158.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quaternised renzapride as a potent and selective 5-HT4 receptor agonist
Year : 1993
Volume : 3
Issue : 4
First Page : 633
Last Page : 634
Authors : Baxter G, Boyland P, Gaster L, King F
|
pKi value for inhibition of [3H]LY-278584 binding to 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
501.19
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biochemical evaluation of tritium-labeled 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxa mide, a useful radioligand for 5HT3 receptors.
Year : 1990
Volume : 33
Issue : 12
First Page : 3176
Last Page : 3181
Authors : Robertson DW, Bloomquist W, Cohen ML, Reid LR, Schenck K, Wong DT.
Abstract : The advent of potent, highly selective 5HT3 receptor antagonists has stimulated considerable interest in 5HT3 receptor mediated physiology and pharmacology. To permit detailed biochemical studies regarding interaction of the indazole class of serotonin (5HT) antagonists with 5HT3 receptors in multiple tissues, we synthesized 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole- 3-carboxamide (LY278584, compound 9) in high specific activity, tritium-labeled form. This radioligand was selected as a synthetic target because of its potency as a 5HT3-receptor antagonist, its selectivity for this receptor viz a viz other 5HT-receptor subtypes, and the ability to readily incorporate three tritia via the indazole N-CH3 substituent. Alkylation of N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxamide (8) with sodium hydride and tritium-labeled iodomethane, followed by HPLC purification, resulted in [3H]-9 with a radiochemical purity of 99% and a specific activity of 80.5 Ci/mmol. This radioligand bound with high affinity to a single class of saturable recognition sites in membranes isolated from cerebral cortex of rat brain. The Kd was 0.69 nM and the Bmax was 16.9 fmol/mg of protein. The specific binding was excellent, and accounted for 83-93% of total binding at concentrations of 2 nM or less. The potencies of known 5HT3-receptor antagonists as inhibitors of [3H]-9 binding correlated well with their pharmacological receptor affinities as antagonists of 5HT-induced decreases in heart rate and contraction of guinea pig ileum, suggesting the central recognition site for this radioligand may be extremely similar to or identical with peripheral 5HT3 receptors.
|
Percent inhibition of apomorphine (0.3 mg/kg) induced emesis in dogs when 1 mg/kg of compound administered perorally
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Binding affinity against dopamine D2 receptor in rat brain synaptic membrane using [3H]-spiperone as radioligand
|
None
|
480.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel series of N-(hexahydro-1,4-diazepin-6-yl) and N-(hexahydroazepin- 3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors.
Year : 1998
Volume : 8
Issue : 6
First Page : 619
Last Page : 624
Authors : Hirokawa Y, Morie T, Yamazaki H, Yoshida N, Kato S.
Abstract : A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine D2 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.
|
Inhibition of [3H]- spiperone binding to rat brain Dopamine receptor D2
|
Rattus norvegicus
|
480.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamides and their affinities for 5-HT3 and dopamine D2 receptors.
Year : 1998
Volume : 8
Issue : 12
First Page : 1551
Last Page : 1554
Authors : Hirokawa Y, Yoshida N, Kato S.
Abstract : A series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamide derivatives were prepared and evaluated for their binding to 5-HT3 and dopamine D2 receptors. Among them, the 5-bromo-2-methoxy-6-methylaminonicotinamide 16 and its (R)-isomer were found to have potent affinities for both receptors. The affinities of (R)-16 for 5-HT3 and dopamine D2 receptors are approximately 3-fold higher than those of the corresponding benzamide (R)-1 (IC50: 1.1 and 12 nM vs. 2.9 and 35 nM, respectively).
|
Compound was evaluated for the binding affinity at Dopamine receptor D2
|
None
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site.
Year : 1995
Volume : 38
Issue : 13
First Page : 2326
Last Page : 2330
Authors : Buchheit KH, Gamse R, Giger R, Hoyer D, Klein F, Klöppner E, Pfannkuche HJ, Mattes H.
Abstract : The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.
|
Evaluated for the dopamine D2 receptor antagonistic activity (antagonism of apomorphine-induced emesis in dogs) at a dose of 3.0 mg/kg administered perorally
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides.
Year : 1990
Volume : 33
Issue : 5
First Page : 1406
Last Page : 1413
Authors : Kato S, Morie T, Hino K, Kon T, Naruto S, Yoshida N, Karasawa T, Matsumoto J.
Abstract : With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.
|
Concentration of compound required to inhibit the binding of radioligand [3H]spiperone to Dopamine receptor D2 in rat brain synaptic membrane
|
None
|
444.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
In vitro antagonistic activity against Dopamine receptor D2 was evaluated for the inhibition of [3H]spiperone binding
|
None
|
565.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted benzamides. 1. Potential nondopaminergic antagonists of chemotherapy-induced nausea and emesis.
Year : 1988
Volume : 31
Issue : 8
First Page : 1548
Last Page : 1558
Authors : Monković I, Willner D, Adam MA, Brown M, Crenshaw RR, Fuller CE, Juby PF, Luke GM, Matiskella JA, Montzka TA.
Abstract : A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).
|
Inhibitory activity against dopamine receptor D2 by 3H ligand binding experiments.
|
None
|
630.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.
Year : 1991
Volume : 34
Issue : 2
First Page : 616
Last Page : 624
Authors : Kato S, Morie T, Kon T, Yoshida N, Karasawa T, Matsumoto J.
Abstract : The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.
|
Inhibitory concentration required for displacing radioligand [3H]SPI from DA D-2 receptor
|
None
|
820.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational analysis of dopamine D-2 receptor antagonists of the benzamide series in relation to a recently proposed D-2 receptor-interaction model.
Year : 1992
Volume : 35
Issue : 13
First Page : 2355
Last Page : 2363
Authors : Pettersson I, Liljefors T.
Abstract : Conformational analysis using molecular mechanics calculations (MM2(87)) has been performed for four different types of benzamides which display high affinity for the dopamine D-2 receptor. In order to elucidate the conformation of the receptor-bound molecules, a previously described dopamine D-2 receptor-interaction model has been employed. We conclude that all four types of benzamides accommodated in the proposed receptor-interaction model are in low-energy conformations. An acyclic amide side chain is concluded to adopt an extended conformation in the receptor-bound benzamide. A phenylpyrrole analogue of the benzamides could similarly be fitted to the model. Using the receptor-interaction model, the enantioselectivity of benzamides with an N-ethyl-2-pyrrolidinylmethyl side chain could be rationalized in terms of different conformational energies of the receptor-bound enantiomers. Two different receptor sites for N-alkyl substituents are suggested.
|
Affinity towards Dopamine receptor D2 in rat striatum using [3H]spiperone as radioligand
|
Rattus norvegicus
|
303.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Binding affinity to dopamine receptor D2
|
None
|
113.0
nM
|
|
Journal : J. Med. Chem.
Title : SC-53116: the first selective agonist at the newly identified serotonin 5-HT4 receptor subtype.
Year : 1992
Volume : 35
Issue : 8
First Page : 1486
Last Page : 1489
Authors : Flynn DL, Zabrowski DL, Becker DP, Nosal R, Villamil CI, Gullikson GW, Moummi C, Yang DC.
|
Binding affinity against Dopamine receptor D2 using [3H]spiperone as radioligand in rat striatum
|
None
|
285.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological activity of a macrocyclic benzamide
Year : 1995
Volume : 5
Issue : 8
First Page : 795
Last Page : 798
Authors : Langlois M, Yang D, Bremont B, Shen S
|
Displacement of [125I]iodosulpiride from human Dopamine receptor D3 expressed in CHO cells
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor: discovery of novel and potent D3 ligands through a hybrid pharmacophore- and structure-based database searching approach.
Year : 2003
Volume : 46
Issue : 21
First Page : 4377
Last Page : 4392
Authors : Varady J, Wu X, Fang X, Min J, Hu Z, Levant B, Wang S.
Abstract : The dopamine 3 (D3) subtype receptor has been implicated in several neurological conditions, and potent and selective D3 ligands may have therapeutic potential for the treatment of drug addiction, Parkinson's disease, and schizophrenia. In this paper, we report computational homology modeling of the D3 receptor based upon the high-resolution X-ray structure of rhodopsin, extensive structural refinement in the presence of explicit lipid bilayer and water environment, and validation of the refined D3 structural models using experimental data. We further describe the development, validation, and application of a hybrid computational screening approach for the discovery of several classes of novel and potent D3 ligands. This computational approach employs stepwise pharmacophore and structure-based searching of a large three-dimensional chemical database for the identification of potential D3 ligands. The obtained hits are then subjected to structural novelty screening, and the most promising compounds are tested in a D3 binding assay. Using this approach we identified four compounds with K(i) values better than 100 nM and eight compounds with K(i) values better than 1 microM out of 20 compounds selected for testing in the D3 receptor binding assay. Our results suggest that the D3 structural models obtained from this study may be useful for the discovery and design of novel and potent D3 ligands. Furthermore, the employed hybrid approach may be more effective for lead discovery from a large chemical database than either pharmacophore-based or structure-based database screening alone.
|
Compound was evaluated for binding affinity towards DA D-2 receptor using radioligand [3H]SPI
|
None
|
104.0
nM
|
|
Compound was evaluated for binding affinity towards DA D-2 receptor using radioligand [3H]SPI
|
None
|
235.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational analysis of dopamine D-2 receptor antagonists of the benzamide series in relation to a recently proposed D-2 receptor-interaction model.
Year : 1992
Volume : 35
Issue : 13
First Page : 2355
Last Page : 2363
Authors : Pettersson I, Liljefors T.
Abstract : Conformational analysis using molecular mechanics calculations (MM2(87)) has been performed for four different types of benzamides which display high affinity for the dopamine D-2 receptor. In order to elucidate the conformation of the receptor-bound molecules, a previously described dopamine D-2 receptor-interaction model has been employed. We conclude that all four types of benzamides accommodated in the proposed receptor-interaction model are in low-energy conformations. An acyclic amide side chain is concluded to adopt an extended conformation in the receptor-bound benzamide. A phenylpyrrole analogue of the benzamides could similarly be fitted to the model. Using the receptor-interaction model, the enantioselectivity of benzamides with an N-ethyl-2-pyrrolidinylmethyl side chain could be rationalized in terms of different conformational energies of the receptor-bound enantiomers. Two different receptor sites for N-alkyl substituents are suggested.
|
Concentration of compound required to inhibit the binding of radioligand [3H](R)-7-OH-DPAT to Dopamine receptor D3 in rat striatum
|
None
|
61.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Tested for PCA activity of compound in rat at 10 mg/kg intravenous dose
|
Rattus norvegicus
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Cloxacepride and related compounds: a new series of orally active antiallergic compounds.
Year : 1983
Volume : 26
Issue : 7
First Page : 1065
Last Page : 1070
Authors : Metz G, Pindell MH, Chen HL.
Abstract : 4-[[(p-Chlorophenoxy)acetyl]amino]-5-chloro-2-methoxy-N-[2-(diethylamino)ethyl]benzamide (cloxacepride, 1), exhibited substantial oral antiallergic potential in a reaginic PCA test in rats over a wide range of antigenic challenge times. Available reference compounds with oral activity, such as doxantrazole and 7-(2-hydroxyethoxy)-9-oxoxanthene-2-carboxylic acid (AH 7725, 4), were active only when administered 15 min before challenge: 4, in particular, was not consistent in effect. Oral ED50 values for cloxacepride of 46-49 mg/kg were comparable to that of theophylline and to an intravenous injection of 2 mg/kg of disodium chromoglycate (DSCG) followed by immediate challenge. Following oral ED50 doses, 1 showed slower onset and longer duration of action than theophylline. The absence of inhibition of systemic anaphylaxis and of antihistaminic activity suggests specific effect or reaginic antigen antibody reactions. Structure-activity relationships of various chemical modifications were investigated and discussed in terms of essential substituents.
|
PCA activity of compound in rat at 100 mg/kg dose
|
Rattus norvegicus
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Cloxacepride and related compounds: a new series of orally active antiallergic compounds.
Year : 1983
Volume : 26
Issue : 7
First Page : 1065
Last Page : 1070
Authors : Metz G, Pindell MH, Chen HL.
Abstract : 4-[[(p-Chlorophenoxy)acetyl]amino]-5-chloro-2-methoxy-N-[2-(diethylamino)ethyl]benzamide (cloxacepride, 1), exhibited substantial oral antiallergic potential in a reaginic PCA test in rats over a wide range of antigenic challenge times. Available reference compounds with oral activity, such as doxantrazole and 7-(2-hydroxyethoxy)-9-oxoxanthene-2-carboxylic acid (AH 7725, 4), were active only when administered 15 min before challenge: 4, in particular, was not consistent in effect. Oral ED50 values for cloxacepride of 46-49 mg/kg were comparable to that of theophylline and to an intravenous injection of 2 mg/kg of disodium chromoglycate (DSCG) followed by immediate challenge. Following oral ED50 doses, 1 showed slower onset and longer duration of action than theophylline. The absence of inhibition of systemic anaphylaxis and of antihistaminic activity suggests specific effect or reaginic antigen antibody reactions. Structure-activity relationships of various chemical modifications were investigated and discussed in terms of essential substituents.
|
Agonist activity against 5-HT4 receptor in rat esophageal muscularis mucosae
|
Rattus norvegicus
|
794.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ketones related to the benzoate 5-HT4 receptor antagonist RS-23597 are high affinity partial agonists
Year : 1994
Volume : 4
Issue : 20
First Page : 2477
Last Page : 2480
Authors : Clark R, Jahangir A, Langston J, Weinhardt K, Miller A, Leung E, Eglen R
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
52.3
%
|
|
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.
|
Mechanism based inhibition of human cytochrome P450 2D6 measured by dextromethorphan O-demethylation
|
Homo sapiens
|
960.0
nM
|
|
Journal : Curr. Drug Metab.
Title : Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
Year : 2005
Volume : 6
Issue : 1
First Page : 413
Last Page : 454
Authors : Fontana E, Dansette PM, Poli SM.
Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
630.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
401.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT3 radioligand binding (ligand: [3H] GR-65630)
|
None
|
902.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: CYP450, 2D6 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
800.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
127.0
nM
|
|
DRUGMATRIX: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
42.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
200.0
nM
|
|
DRUGMATRIX: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
68.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
708.0
nM
|
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
472.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Radioligand Binding Assay: The pharmacological profile of metopimazine, metopimazine acid (MPZA), domperidone, and metoclopramide were assessed by radioligand binding and by a functional antagonist assay. For the radioligand binding assay, cell membranes of dopamine D2 receptor expressing cells were incubated with [3H]spiperone and competing drugs in buffer. The assay was terminated by rapid filtration, and the bound radioactive signal was determined by liquid scintillation counting.
|
Homo sapiens
|
64.0
nM
|
|
Title : Methods for treating GI tract disorders
Year : 2015
|
Radioligand Binding Assay: The pharmacological profile of metopimazine, metopimazine acid (MPZA), domperidone, and metoclopramide were assessed by radioligand binding and by a functional antagonist assay. For the radioligand binding assay, cell membranes of dopamine D2 receptor expressing cells were incubated with [3H]spiperone and competing drugs in buffer. The assay was terminated by rapid filtration, and the bound radioactive signal was determined by liquid scintillation counting.
|
Homo sapiens
|
16.0
nM
|
|
Title : Methods for treating GI tract disorders
Year : 2015
|
Inhibition of recombinant MPO (unknown origin) assessed as reduction in taurine chloramine production preincubated with enzyme and taurine followed by H2O2 addition measured after 5 mins
|
Homo sapiens
|
350.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure.
Year : 2017
Volume : 60
Issue : 15
First Page : 6563
Last Page : 6586
Authors : Soubhye J, Chikh Alard I, Aldib I, Prévost M, Gelbcke M, De Carvalho A, Furtmüller PG, Obinger C, Flemmig J, Tadrent S, Meyer F, Rousseau A, Nève J, Mathieu V, Zouaoui Boudjeltia K, Dufrasne F, Van Antwerpen P.
Abstract : The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.65
%
|
|
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
|
-0.09
%
|
|
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
|
-0.09
%
|
|
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.
