Phenylimidazolidin-2-one Derivatives as Selective 5-HT3 Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT3 Receptor Binding

• Published in: Journal of medicinal chemistry 1997-10, Vol.40 (21), p.3369-3380
• Main Authors: Heidempergher, Franco, Pillan, Antonio, Pinciroli, Vittorio, Vaghi, Fabrizio, Arrigoni, Claudio, Bolis, Giorgio, Caccia, Carla, Dho, Luciano, McArthur, Robert, Varasi, Mario
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - drug effects; Guinea Pigs; Heart Rate - drug effects; Ileum - drug effects; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Muscles - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT3; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - metabolism; Serotonin Antagonists - pharmacology; Serotoninergic system
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970060o

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.