STEREOELECTRONIC REQUIREMENTS OF BENZAMIDE 5HT(3) ANTAGONISTS - COMPARISON WITH D-2 ANTIDOPAMINERGIC ANALOGS

Renzapride (I) and Tropapride (IV) are very similar substituted benzam ides but are distinguishable by their pharmacological profile: the for mer is a potent 5HT(3) antagonist while the latter is a very active D- 2 antidopaminergic drug. A combination of experimental methods (X-ray diffraction and H-1 NMR spectroscopy) and theoretical calculations (se miempirical molecular orbital AM1) were used to investigate the confor mational space of three 5HT(3) antagonists: Renzapride (I, BRL24924), DAU6215 (II) and Ondansetron (III, GR38032). The analysis of their sol id state conformations as well as their isolated state structures allo ws us to propose a 5HT(3) pharmacophoric model which is compared to th e one previously reported for benzamide D-2 antagonists, represented b y Tropapride (IV).