Stereoelectronic requirements of benzamide 5HT3 antagonists. Comparison with D2 antidopaminergic analogues
Abstract
Renzapride (I) and Tropapride (IV) are very similar substituted benzamides but are distinguishable by their pharmacological profile: the former is a potent 5HT3 antagonist while the latter is a very active D2 antidopaminergic drug. A combination of experimental methods (X-ray diffraction and 1H NMR spectroscopy) and theoretical calculations (semiempirical molecular orbital AM1) were used to investigate the conformational space of three 5HT3 antagonists: Renzapride (I, BRL24924), DAU6215 (II) and Ondansetron (III, GR38032). The analysis of their solid state conformations as well as their isolated state structures allows us to propose a 5HT3 pharmacophoric model which is compared to the one previously reported for benzamide D2 antagonists, represented by Tropapride (IV).
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