PHENYLIMIDAZOLIDIN-2-ONE DERIVATIVES AS SELECTIVE 5-HT3 RECEPTOR ANTAGONISTS AND REFINEMENT OF THE PHARMACOPHORE MODEL FOR 5-HT3 RECEPTOR-BINDING

A possible bioisosterism between the benzamido and the phenylimidazoli din-2-one moieties has been suggested on the basis of the similarity b etween the molecular electrostatic potential (MEP) of metoclopramide, a D-2 receptor antagonist with weak 5-HT3 receptor antagonist properti es, and zetidoline, a D-2 receptor antagonist. Starting from this prem ise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and eval uated for 5-HT3 receptor radioligand binding affinity ([H-3]- GR 43694 ). In vitro 5-HT3 receptor antagonist activity was tested in the guine a pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhib ition of the Bezold-Jarisch reflex in the anesthetized rat. In general , the imidazolylalkyl derivatives were found to be more active than az abicycloalkyls. -3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazolidin -2- one (58), in particular, displayed very high affinity for the 5-HT3 re ceptor (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, g ranisetron, and BRL 46470) tested. 58 showed an ID50 comparable to tha t of ondansetron (2.2 mu g/kg iv) in the Bezold-Jarisch reflex. A mole cular modeling study based on this structurally novel series of compou nds allowed the refinement of previously reported 5-HT3 receptor antag onist pharmacophore models.