Structural analysis of 5-HT3 receptor antagonists: Synthesis and pharmacological activity of various aromatic esters or amides derived from tropane and 1,2,6-trisubstituted piperidine

Article abstract of DOI:10.1016/0223-5234(93)90039-H

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