Synthesis of quinazoline-2,4-dione and naphthalimide derivatives as new 5-HT3 receptor antagonists

Article abstract of DOI:10.1016/0223-5234(94)90192-9

New potent 5-HT₃ receptor antagonists have been designed from the naphthalimide moiety and a quinuclidine heterocycle and the structure-activity relationships are discussed here on the basis of the nature of the substituent on the aromatic system. The biological activity of the compounds was evaluated in binding assays with [³H]BRL-43694 and by inhibition of the Bezold-Jarisch reflex. Compound 22 with a 4-amino substituent was equipotent to the reference compounds. In contrast to the benzamide derivatives, the activity resides essentially in the (R) enantiomer (K(i) = 0.15 ± 0.05 nM, ID₅₀ = 1.6 μg/kg/iv) and it is demonstrated that the additional carbonyl group is involved in the inversion of the enantioselectivity of the receptor. Conformational studies of (R)-22 demonstrated the presence of a locked structure with 4 minimal energy conformers which were compared to those of (S)-zacopride. The superimposition of the putative active conformers emphasized the presence of a second polar group in the binding site. The fluorescent properties of the compounds were studied and indicate that (R)-22 and its derivatives may be promising tools for the direct visualization of 5-HT₃ receptors.