|
Binding affinity towards rat 5-hydroxytryptamine 3 receptor was evaluated
|
None
|
1.55
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacology of isoquinuclidine derivatives as 5-HT(3) ligands.
Year : 2002
Volume : 12
Issue : 2
First Page : 189
Last Page : 192
Authors : Iriepa I, Villasante FJ, Gálvez E, Labeaga L, Innerarity A, Orjales A.
Abstract : A series of 4-amino-5-chloro-2-methoxybenzoates and benzamides containing the 5- and 6-isoquinuclidinyl system was synthesised and evaluated for binding to 5-HT(3), 5-HT(4) and D(2) receptors. In general, the isoquinuclidine derivatives at the 5-position have shown to be more potent as 5-HT(3) ligands but they also possess 5-HT(4) and D(2) properties. However, the results show that the derivatives at the 6-position afforded the most promising compounds in terms of both receptor affinity and selectivity.
|
Compound was evaluated for its binding affinity for 5-hydroxytryptamine 3 receptor by measuring displacement [3H]GR-65630 in rat cerebral cortex
|
None
|
3.2
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.
|
In vitro affinity for 5-hydroxytryptamine 3 (5-HT3) receptor by displacement of [3H]BRL-43694 from rat entorhinal cortex
|
None
|
1.57
nM
|
|
Journal : J. Med. Chem.
Title : Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding.
Year : 1997
Volume : 40
Issue : 21
First Page : 3369
Last Page : 3380
Authors : Heidempergher F, Pillan A, Pinciroli V, Vaghi F, Arrigoni C, Bolis G, Caccia C, Dho L, McArthur R, Varasi M.
Abstract : A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.
|
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
|
1.28
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.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 0.3 mg/kg at 0.5 hours in urethane-anesthetized rats
|
None
|
86.6
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 0.3 mg/kg at 1 hour in urethane-anesthetized rats
|
None
|
7.4
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 0.3 mg/kg at 3 hours in urethane-anesthetized rats
|
None
|
65.2
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 0.3 mg/kg at 6 hours in urethane-anesthetized rats
|
None
|
17.4
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Binding affinity to 5-hydroxytryptamine 3 receptor entirely in guinea pig ileum
|
Cavia porcellus
|
12.59
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.
|
Antagonistic activity against Serotonin 5-hydroxytryptamine 3 receptor of isolated guinea pig ileum (GPI)
|
Cavia porcellus
|
12.59
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
|
The binding affinity was measured for 5-hydroxytryptamine 3 receptor on NG 108-15 cell line of mouse neuroblastoma-glioma cells in presence of [3H]5 radioligand (in vitro)
|
None
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, in vitro binding profile, and central nervous system penetrability of the highly potent 5-HT3 receptor antagonist [3H]-4-(2-methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole.
Year : 1990
Volume : 33
Issue : 11
First Page : 3020
Last Page : 3023
Authors : Rosen T, Seeger TF, McLean S, Nagel AA, Ives JL, Guarino KJ, Bryce D, Furman J, Roth RW, Chalabi PM.
Abstract : 4-(2-Methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole (5) is a highly potent member of a structurally novel series of selective serotonin-3 receptor antagonists. The synthesis of tritiated 5 and its binding profile in neuroblastoma-glioma 108-15 cells are described. Furthermore, in vivo studies in rat with this radioligand indicate that it effectively penetrates the blood-brain barrier upon peripheral administration. Thus, 5 should be a useful pharmacological tool for both in vitro and in vivo studies of this class of compounds.
|
Binding affinity to 5-hydroxytryptamine 3 receptor of neuronal in the afferent rabbit vagus
|
Oryctolagus cuniculus
|
0.0631
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.
|
Potency at neuronal 5-hydroxytryptamine 3 receptor in the rabbit heart
|
Oryctolagus cuniculus
|
106.0
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
|
0.02512
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
|
0.0631
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
|
In vitro displacement of [3H]-LY 278584 from rat cerebral cortex 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
1.28
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel benzimidazole-4-carboxylic acid derivatives as potent and selective 5-HT3 receptor ligands
Year : 1996
Volume : 6
Issue : 11
First Page : 1195
Last Page : 1198
Authors : Lopez-Rodriguez ML, Morcillo MJ, Benhamu B, Riaguas MD
|
In vitro displacement of [3H]ICS-205-930 from 5-hydroxytryptamine 3 receptor in cultured NG-108-15 rat glioma cells
|
Rattus norvegicus
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Aromatic thiazole derivatives: structurally novel and selective serotonin-3 receptor antagonists.
Year : 1990
Volume : 33
Issue : 1
First Page : 13
Last Page : 16
Authors : Nagel AA, Rosen T, Rizzi J, Daffeh J, Guarino K, Nowakowski J, Vincent LA, Heym J, McLean S, Seeger T.
|
Inhibition of 5-HT (1 ug/mL) induced depolarization in rat vagus nerve (5-hydroxytryptamine 3 receptor antagonism)
|
Rattus norvegicus
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrazolo[1,5-a]pyridines and pyrazolo[1,5-b]pyridazines as 5ht3-antagonists
Year : 1994
Volume : 4
Issue : 5
First Page : 695
Last Page : 698
Authors : Bondo Hansen J, Weis J, Suzdak P, Eskesen K
|
Binding affinity was evaluated in vitro by displacement of [3H]zacopride radioligand from 5-hydroxytryptamine 3 receptor
|
None
|
2.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azaheteroaromatic ethers as carbonyl bioisosteres. Synthesis and evaluation of a novel class of 5-HT3 receptor antagonists
Year : 1992
Volume : 2
Issue : 3
First Page : 245
Last Page : 248
Authors : Cliffe IA, Brammer N, Middlefell V, Swaminathan P, White AC
|
Inhibition of [3H]GR-65630 binding to rat cortical membrane serotonin 3 receptor
|
Rattus norvegicus
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrazolo[1,5-a]pyridines and pyrazolo[1,5-b]pyridazines as 5ht3-antagonists
Year : 1994
Volume : 4
Issue : 5
First Page : 695
Last Page : 698
Authors : Bondo Hansen J, Weis J, Suzdak P, Eskesen K
|
5-hydroxytryptamine 3 receptor antagonistic activity measured by inhibition of 5-HT-induced bradycardia (iv administration 10 ug/kg dose in urethane-anesthetized rats)
|
None
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
5-hydroxytryptamine 3 receptor antagonistic activity as inhibition of 5-HT-induced bradycardia after iv administration of 100 ug/kg dose in urethane-anesthetized rats
|
Rattus norvegicus
|
70.6
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
5-hydroxytryptamine 3 receptor antagonistic activity was measured by the inhibition of 5H+ T-induced bradycardia after iv administration of 3 ug/kg dose in urethane-anesthetized rats
|
None
|
54.2
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after intravenous administration of 1 ug/kg dose in urethane-anesthetized rats
|
None
|
20.1
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 10 ug/kg dose in urethane-anesthetized rats
|
None
|
0.1
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 100 ug/kg dose in urethane-anesthetized rats
|
None
|
39.8
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 1000 ug/kg dose in urethane-anesthetized rats
|
None
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Compound was tested for the inhibition of 5-HT-induced bradycardia after peroral administration of 300 ug/kg dose in urethane-anesthetized rats
|
None
|
77.4
%
|
|
Journal : J. Med. Chem.
Title : Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Year : 1992
Volume : 35
Issue : 2
First Page : 310
Last Page : 319
Authors : Robertson DW, Lacefield WB, Bloomquist W, Pfeifer W, Simon RL, Cohen ML.
Abstract : Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
|
Serotonin receptor antagonist activity was measured as ability to block the serotonin-induced Bezold-Jarisch reflex in rats after iv administration of 10 ug/Kg
|
None
|
77.5
%
|
|
Journal : J. Med. Chem.
Title : Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists.
Year : 1990
Volume : 33
Issue : 10
First Page : 2715
Last Page : 2720
Authors : Rosen T, Nagel AA, Rizzi JP, Ives JL, Daffeh JB, Ganong AH, Guarino K, Heym J, McLean S, Nowakowski JT.
Abstract : A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.
|
Tested for inhibition of Bezold-Jarisch (B-J) reflex mediated by 5-hydroxytryptamine 3 receptor in rats after intravenous administration (2.0 ug/kg)
|
None
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : An initial three-component pharmacophore for specific serotonin-3 receptor ligands.
Year : 1990
Volume : 33
Issue : 10
First Page : 2721
Last Page : 2725
Authors : Rizzi JP, Nagel AA, Rosen T, McLean S, Seeger T.
Abstract : With computer modeling, an initial three-component pharmacophore for specific 5-HT3 receptor ligands ICS-205-930 (1), ondansetron (2), zacopride (3), and 3-[2-(guanidinylmethyl)-4-thiazolyl]indol (4) has been identified. Two parts represent electrostatic interactions, one as a hydrogen-bond-donating interaction and the other as a hydrogen-bond-accepting interaction. The third part is represented by a plane in which the lipophilic aromatic groups align. The generation of the pharmacophore relies on the interactions of these ligands with probe atoms representative of a possible hydrogen-bond donor or hydrogen-bond acceptor within the receptor. A carboxylate oxygen was used as a hydrogen-bond-accepting probe and a serine-like hydroxyl was utilized as a hydrogen-bond-donating probe.
|
Binding affinity towards 5-hydroxytryptamine 4 receptor in striatum membranes of guinea-pig brain was evaluated
|
Cavia porcellus
|
125.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacology of isoquinuclidine derivatives as 5-HT(3) ligands.
Year : 2002
Volume : 12
Issue : 2
First Page : 189
Last Page : 192
Authors : Iriepa I, Villasante FJ, Gálvez E, Labeaga L, Innerarity A, Orjales A.
Abstract : A series of 4-amino-5-chloro-2-methoxybenzoates and benzamides containing the 5- and 6-isoquinuclidinyl system was synthesised and evaluated for binding to 5-HT(3), 5-HT(4) and D(2) receptors. In general, the isoquinuclidine derivatives at the 5-position have shown to be more potent as 5-HT(3) ligands but they also possess 5-HT(4) and D(2) properties. However, the results show that the derivatives at the 6-position afforded the most promising compounds in terms of both receptor affinity and selectivity.
|
Displacement of [3H]GR-113808 from rat striatum 5-hydroxytryptamine 4 receptor
|
Rattus norvegicus
|
63.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel benzimidazole-4-carboxylic acid derivatives as potent and selective 5-HT3 receptor ligands
Year : 1996
Volume : 6
Issue : 11
First Page : 1195
Last Page : 1198
Authors : Lopez-Rodriguez ML, Morcillo MJ, Benhamu B, Riaguas MD
|
Compound was evaluated for the displacement of [3H]Q-ICS-205-930 from 5-HT3 recognition sites in rat brain membranes
|
None
|
1.259
nM
|
|
Journal : J. Med. Chem.
Title : Novel 5-HT3 antagonists: indol-3-ylspiro(azabicycloalkane-3,5'(4'H)-oxazoles).
Year : 1992
Volume : 35
Issue : 6
First Page : 1019
Last Page : 1031
Authors : Swain CJ, Baker R, Kneen C, Herbert R, Moseley J, Saunders J, Seward EM, Stevenson GI, Beer M, Stanton J.
Abstract : The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.
|
Binding affinity to 5-hydroxytryptamine 3 receptor using [3H]GR-65630 as radioligand in rat cortex
|
None
|
3.162
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
|
0.6026
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.
|
In vitro by displacement of [3H]LY-278584 from 5-hydroxytryptamine 3 receptor on rat entorhinal cortex
|
None
|
1.585
nM
|
|
Journal : J. Med. Chem.
Title : New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation.
Year : 1997
Volume : 40
Issue : 4
First Page : 586
Last Page : 593
Authors : Orjales A, Mosquera R, Labeaga L, Rodes R.
Abstract : A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pKi = 9.2) exhibited higher affinity for the 5-HT3 receptor than did tropisetron and granisetron, while compound 7q (pKi = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pKi = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pKi = 9.4). Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.
|
pKi value for inhibition of [3H]LY-278584 binding to 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
1.288
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.
|
Concentration that inhibits the binding of radioligand, [3H]-ICS 205930, to 5-hydroxytryptamine 3 receptor from rat cortex
|
None
|
1.71
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists.
Year : 1990
Volume : 33
Issue : 8
First Page : 2101
Last Page : 2108
Authors : Turconi M, Nicola M, Quintero MG, Maiocchi L, Micheletti R, Giraldo E, Donetti A.
Abstract : A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid esters and amides containing a basic azacyclo- or azabicycloalkyl moiety has been synthesized and evaluated for 5-HT3 antagonistic activity in a radioligand binding assay ([3H]ICS 205930) and in the 5-HT-induced von Bezold-Jarisch reflex in the rat. It was found that endo-substituted azabicycloalkyl derivatives (e.g. 7a, 12a, 12b) were much more active than the corresponding exo analogues (e.g. 7b, 12h, 12i) or azacycloalkyl compounds. Amidic derivatives 12a, 12b, 12c, 12e, 13b, and 13c proved to be about 10 times more active than the corresponding ester derivatives 7a, 11a, 7c, 7d, 8a, and 8b. In particular, compound 12a (DA 6215) showed a Ki = 3.8 nM in the binding test and an ED50 = 1 nM/kg iv in the von Bezold-Jarisch reflex assay, an activity comparable to that of the reference compound 2 (ICS 205930, Ki = 2 nM, ED50 = 2.1 nM/kg). IR spectroscopy studies in the solid state and in CHCl3 solution revealed the existence of an intramolecular hydrogen bond in 13b, taken as a model compound for this class of substances. A molecular modeling study showed that 12a, in its internal hydrogen-bound conformation, well matches a recently proposed pharmacophoric model for 5-HT3 antagonist activity.
|
Binding affinity against 5-hydroxytryptamine 3 (5-HT3) receptor in rat brain cortical membranes using radioligand [3H]quipazine
|
None
|
1.995
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists.
Year : 1993
Volume : 36
Issue : 18
First Page : 2645
Last Page : 2657
Authors : Clark RD, Miller AB, Berger J, Repke DB, Weinhardt KK, Kowalczyk BA, Eglen RM, Bonhaus DW, Lee CH, Michel AD.
Abstract : Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.
|
Binding affinity of compound towards 5-hydroxytryptamine 3 receptor using [3H]-BRL-43694 (1 nM) ligand in NG cells 108-15 was determined
|
None
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
In vitro Binding affinity towards 5-hydroxytryptamine 3 receptor was determined
|
None
|
5.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist.
Year : 2001
Volume : 11
Issue : 3
First Page : 319
Last Page : 321
Authors : Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC.
Abstract : The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors.
|
Binding affinity towards 5-hydroxytryptamine 3 receptor by displacement of [3H]2 in Neuroblastoma-Glioma NG-108-15 cells
|
None
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists.
Year : 1990
Volume : 33
Issue : 10
First Page : 2715
Last Page : 2720
Authors : Rosen T, Nagel AA, Rizzi JP, Ives JL, Daffeh JB, Ganong AH, Guarino K, Heym J, McLean S, Nowakowski JT.
Abstract : A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.
|
In vitro binding affinity for the 5-hydroxytryptamine 3 receptor was determined with NG-108-15 mouse neuroblastoma-glioma cells
|
None
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : An initial three-component pharmacophore for specific serotonin-3 receptor ligands.
Year : 1990
Volume : 33
Issue : 10
First Page : 2721
Last Page : 2725
Authors : Rizzi JP, Nagel AA, Rosen T, McLean S, Seeger T.
Abstract : With computer modeling, an initial three-component pharmacophore for specific 5-HT3 receptor ligands ICS-205-930 (1), ondansetron (2), zacopride (3), and 3-[2-(guanidinylmethyl)-4-thiazolyl]indol (4) has been identified. Two parts represent electrostatic interactions, one as a hydrogen-bond-donating interaction and the other as a hydrogen-bond-accepting interaction. The third part is represented by a plane in which the lipophilic aromatic groups align. The generation of the pharmacophore relies on the interactions of these ligands with probe atoms representative of a possible hydrogen-bond donor or hydrogen-bond acceptor within the receptor. A carboxylate oxygen was used as a hydrogen-bond-accepting probe and a serine-like hydroxyl was utilized as a hydrogen-bond-donating probe.
|
In vitro Binding affinity towards alpha-7 nAChR was determined
|
None
|
6.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist.
Year : 2001
Volume : 11
Issue : 3
First Page : 319
Last Page : 321
Authors : Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC.
Abstract : The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors.
|
Activation responses to that evoked by ACh at human Nicotinic acetylcholine receptor alpha-7 expressed in xenopus oocytes
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Activity of alpha7-selective agonists at nicotinic and serotonin 5HT3 receptors expressed in Xenopus oocytes.
Year : 2004
Volume : 14
Issue : 8
First Page : 1849
Last Page : 1853
Authors : Papke RL, Porter Papke JK, Rose GM.
Abstract : Nicotinic receptors containing alpha7 subunits are widely distributed in the central nervous system and are thought to be involved in a number of functions. However, it has been difficult to study alpha7-containing receptors in vivo because of a paucity of selective agonists. A new spirooxazolidinone compound, AR-R17779, was recently described as potent agonist at alpha7 receptors, but electrophysiological studies at other types of nicotinic receptors have not been carried out. We characterized the activity of AR-R17779 at alpha7, alpha4beta2, alpha3beta4, alpha3beta2, alpha3beta2alpha5 receptors expressed in Xenopus oocytes. In addition, since there is significant homology between nicotinic alpha7 and serotonin 5HT(3) receptors, the activity of AR-R17779 at expressed 5HT(3a) receptors was also examined. Finally, actions of tropisetron and ondansetron, two 5HT(3) antagonists, were explored. AR-R17779 was found to activate alpha7 receptors, but had no activity at other types of nicotinic receptors, and also had no activity at 5HT(3a) receptors. Tropisetron activated, while ondansetron acted as an antagonist, at alpha7 nicotinic receptors. The two 5HT(3) antagonists also acted as antagonists at alpha4beta2 and alpha3beta4 nicotinic receptors. Thus, AR-R17779 was confirmed to be a selective nicotinic alpha7 receptor agonist and to be without activity at 5HT(3) receptors. In contrast, the actions of tropisetron and ondansetron on nicotinic receptors were complex.
|
Antagonist activity (100 mg/Kg) for the Bezold Jarisch reflex evoked by 30(mg/Kg) of 5-HT in ethylurethane anesthetized rats (i.v.)
|
Rattus norvegicus
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding.
Year : 1997
Volume : 40
Issue : 21
First Page : 3369
Last Page : 3380
Authors : Heidempergher F, Pillan A, Pinciroli V, Vaghi F, Arrigoni C, Bolis G, Caccia C, Dho L, McArthur R, Varasi M.
Abstract : A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.
|
Percent inhibition of serotonin-induced B-J reflex (Bezold-Jarisch reflex)in the right femoral vein of rat at a dose of 2 ug/kg
|
Rattus norvegicus
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : Aromatic thiazole derivatives: structurally novel and selective serotonin-3 receptor antagonists.
Year : 1990
Volume : 33
Issue : 1
First Page : 13
Last Page : 16
Authors : Nagel AA, Rosen T, Rizzi J, Daffeh J, Guarino K, Nowakowski J, Vincent LA, Heym J, McLean S, Seeger T.
|
Percentage inhibition 5-HT- mediated bradycardia in rat after 3 ug/Kg of compound administered intravenously
|
Rattus norvegicus
|
66.0
%
|
|
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 constant against 5-hydroxytryptamine 1A receptor
|
Homo sapiens
|
5.3
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
|
Inhibition constant against nicotinic acetylcholine receptor alpha7
|
Homo sapiens
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
|
Antagonist activity at 5HT3 receptor in spontaneously beating guinea pig right atrium assessed as inhibition of serotonin-induced maximum response by competitive binding assay
|
Cavia porcellus
|
30.2
nM
|
|
Journal : J. Med. Chem.
Title : Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships.
Year : 2009
Volume : 52
Issue : 11
First Page : 3548
Last Page : 3562
Authors : Morelli E, Gemma S, Budriesi R, Campiani G, Novellino E, Fattorusso C, Catalanotti B, Coccone SS, Ros S, Borrelli G, Persico M, Fiorini I, Nacci V, Ioan P, Chiarini A, Hamon M, Cagnotto A, Mennini T, Fracasso C, Colovic M, Caccia S, Butini S.
Abstract : The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.
|
Binding affinity at 5HT3 receptor
|
None
|
2.818
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel antagonists of serotonin-4 receptors: synthesis and biological evaluation of pyrrolothienopyrazines.
Year : 2009
Volume : 17
Issue : 6
First Page : 2607
Last Page : 2622
Authors : Lemaître S, Lepailleur A, Bureau R, Butt-Gueulle S, Lelong-Boulouard V, Duchatelle P, Boulouard M, Dumuis A, Daveu C, Lezoualc'h F, Pfeiffer B, Dauphin F, Rault S.
Abstract : Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.
|
Binding affinity at 5HT4 receptor
|
None
|
199.53
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel antagonists of serotonin-4 receptors: synthesis and biological evaluation of pyrrolothienopyrazines.
Year : 2009
Volume : 17
Issue : 6
First Page : 2607
Last Page : 2622
Authors : Lemaître S, Lepailleur A, Bureau R, Butt-Gueulle S, Lelong-Boulouard V, Duchatelle P, Boulouard M, Dumuis A, Daveu C, Lezoualc'h F, Pfeiffer B, Dauphin F, Rault S.
Abstract : Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT3 radioligand binding (ligand: [3H] GR-65630)
|
None
|
6.76
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT3 radioligand binding (ligand: [3H] GR-65630)
|
None
|
1.519
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-HT4 radioligand binding (ligand: [3H] GR-113808)
|
Cavia porcellus
|
324.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT4 radioligand binding (ligand: [3H] GR-113808)
|
Cavia porcellus
|
54.0
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: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
488.0
nM
|
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
259.0
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: GABAA, Flunitrazepam, Central radioligand binding (ligand: [3H] Flunitrazepam)
|
Rattus norvegicus
|
926.0
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
|
Inhibition of 5HT3 receptor
|
None
|
5.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of α7 nicotinic acetylcholine receptor modulators.
Year : 2011
Volume : 54
Issue : 23
First Page : 7943
Last Page : 7961
Authors : Mazurov AA, Speake JD, Yohannes D.
|
Binding affinity to alpha7 nAChR
|
None
|
6.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of α7 nicotinic acetylcholine receptor modulators.
Year : 2011
Volume : 54
Issue : 23
First Page : 7943
Last Page : 7961
Authors : Mazurov AA, Speake JD, Yohannes D.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-1.89
%
|
|
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
|
-0.02
%
|
|
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
|
-0.02
%
|
|
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.
