Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding

Franco Heidempergher, Antonio Pillan, Vittorio Pinciroli, Fabrizio Vaghi, Claudio Arrigoni, Giorgio Bolis, Carla Caccia, Luciano Dho, Robert McArthur, Mario Varasi

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 43694). 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]imidazolidin-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (K(i) of 0.038 nM) with a K(b) of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 μg/kg iv) 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.

Original languageEnglish
Pages (from-to)3369-3380
Number of pages12
JournalJournal of Medicinal Chemistry
Volume40
Issue number21
DOIs
Publication statusPublished - 1997

Fingerprint

Serotonin 5-HT3 Receptor Antagonists
Receptors, Serotonin, 5-HT3
Derivatives
Ondansetron
Assays
tropisetron
4-methylimidazole
Ileum
Reflex
Guinea Pigs
Bearings (structural)
Granisetron
Metoclopramide
Molecular modeling
Static Electricity
Rats
Electrostatics
Ligands

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding. / Heidempergher, Franco; Pillan, Antonio; Pinciroli, Vittorio; Vaghi, Fabrizio; Arrigoni, Claudio; Bolis, Giorgio; Caccia, Carla; Dho, Luciano; McArthur, Robert; Varasi, Mario.

In: Journal of Medicinal Chemistry, Vol. 40, No. 21, 1997, p. 3369-3380.

Research output: Contribution to journalArticle

Heidempergher, F, Pillan, A, Pinciroli, V, Vaghi, F, Arrigoni, C, Bolis, G, Caccia, C, Dho, L, McArthur, R & Varasi, M 1997, 'Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding', Journal of Medicinal Chemistry, vol. 40, no. 21, pp. 3369-3380. https://doi.org/10.1021/jm970060o
Heidempergher, Franco ; Pillan, Antonio ; Pinciroli, Vittorio ; Vaghi, Fabrizio ; Arrigoni, Claudio ; Bolis, Giorgio ; Caccia, Carla ; Dho, Luciano ; McArthur, Robert ; Varasi, Mario. / Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 21. pp. 3369-3380.
@article{bafd1c375113499cbc7d4d6d5697a4ab,
title = "Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding",
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 43694). 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]imidazolidin-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (K(i) of 0.038 nM) with a K(b) of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 μg/kg iv) 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.",
author = "Franco Heidempergher and Antonio Pillan and Vittorio Pinciroli and Fabrizio Vaghi and Claudio Arrigoni and Giorgio Bolis and Carla Caccia and Luciano Dho and Robert McArthur and Mario Varasi",
year = "1997",
doi = "10.1021/jm970060o",
language = "English",
volume = "40",
pages = "3369--3380",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

TY - JOUR

T1 - Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding

AU - Heidempergher, Franco

AU - Pillan, Antonio

AU - Pinciroli, Vittorio

AU - Vaghi, Fabrizio

AU - Arrigoni, Claudio

AU - Bolis, Giorgio

AU - Caccia, Carla

AU - Dho, Luciano

AU - McArthur, Robert

AU - Varasi, Mario

PY - 1997

Y1 - 1997

N2 - 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 43694). 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]imidazolidin-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (K(i) of 0.038 nM) with a K(b) of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 μg/kg iv) 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.

AB - 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 43694). 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]imidazolidin-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (K(i) of 0.038 nM) with a K(b) of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 μg/kg iv) 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.

UR - http://www.scopus.com/inward/record.url?scp=9844255572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9844255572&partnerID=8YFLogxK

U2 - 10.1021/jm970060o

DO - 10.1021/jm970060o

M3 - Article

VL - 40

SP - 3369

EP - 3380

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -