SYNTHESIS OF QUINAZOLINE-2,4-DIONE AND NAPHTHALIMIDE DERIVATIVES AS NEW 5-HT3 RECEPTOR ANTAGONISTS

New potent 5-HT3 receptor antagonists have been designed from the naph thalimide moiety and a quinuclidine heterocycle and the structure-acti vity relationships are discussed here on the basis of the nature of th e substituent on the aromatic system. The biological activity of the c ompounds was evaluated in binding assays with [H-3]BRL-43694 and by in hibition of the Bezold-Jarisch reflex. Compound 22 with a 4-amino subs tituent was equipotent to the reference compounds. In contrast to the benzamide derivatives, the activity resides essentially in the (R) ena ntiomer (K-i = 0.15 +/- 0.05 nM, ID50 = 1.6 mu g/kg/iv) and it is demo nstrated that the additional carbonyl group is involved in the inversi on of the enantioselectivity of the receptor. Conformational studies o f (R)-22 demonstrated the presence of a locked structure with 4 minima l energy conformers which were compared to those of (S)-zacopride. The superimposition of the putative active conformers emphasized the pres ence of a second polar group in the binding site. The fluorescent prop erties of the compounds were studied and indicate that (R)-22 and its derivatives may be promising tools for the direct visualization of 5-H T3 receptors.