STRUCTURAL-ANALYSIS OF 5-HT(3) RECEPTOR ANTAGONISTS - SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF VARIOUS AROMATIC ESTERS OR AMIDES DERIVED FROM TROPANE AND 1,2,6-TRISUBSTITUTED PIPERIDINE

Preliminary results of a structure-activity relationship in the field of 5-HT3 receptor antagonists on the influence of the aromatic ring an d steric hindrance around the basic nitrogen atom are reported. The fa vorable role of the naphthalene moiety substituted by a carbonyl funct ion in position 1 was demonstrated by measuring the biological activit y using the inhibition of the specific binding of [H-3]BRL 43694 and t he inhibition of the Bezold-Jarisch reflex. Several esters and amides of 1,2,6-trisubstituted piperidine derivatives with a suitable fit wit h the antagonist reference compounds were synthesized. The lack of bio logical activity of these compounds emphasizes the importance of steri c hindrance for binding with the anionic receptor site. These data con firm the major role of the tropane and quinuclidine frameworks in the potency of a number of 5-HT3 antagonists.