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 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.
authors.affiliation: CNS Research, Structure Based Drug Design-CAMD Unit, Pharmacia & Upjohn, Nerviano, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Heidempergher
authors.forename: A
authors.initials: A
authors.lastname: Pillan
authors.forename: V
authors.initials: V
authors.lastname: Pinciroli
authors.forename: F
authors.initials: F
authors.lastname: Vaghi
authors.forename: C
authors.initials: C
authors.lastname: Arrigoni
authors.forename: G
authors.initials: G
authors.lastname: Bolis
authors.forename: C
authors.initials: C
authors.lastname: Caccia
authors.forename: L
authors.initials: L
authors.lastname: Dho
authors.forename: R
authors.initials: R
authors.lastname: McArthur
authors.forename: M
authors.initials: M
authors.lastname: Varasi
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009132:Muscles / Q000187:drug effects; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists