Medicinal Chemistry of 5-HT4 Receptor Ligands

Abstract

The discovery and classification of the 5-HT4 receptor was greatly facilitated by identification of ligands that interacted with this receptor and that provided tools for the elucidation of receptor signaling and function. Thus tropisetron (ICS-205 930,1⋆) was found to be a weak antagonist of 5-HT induced stimulation of adenylate cyclase activity in primary cultures of mouse embryo colliculi neurones with an apparent inhibition constant (Ki) of 997 nM.1 Tropisetron was also reported to inhibit 5-HT stimulated adenylate cyclase activity in guinea pig hippocampus with a pKi of 7.6,2 and the connection thereby established between the 5-HT receptor responsible for the observed activity in these two CNS preparations was largely responsible for the proposed classification of the 5-HT4 receptor (for reviews see refs. 3–5). The subsequent finding that certain members of the benzamide family of gastrointestinal prokinetic agents were agonists of the 5-HT4 receptor in mouse embryo colliculi neurones6 and in guinea pig hippocampus7 represented the first step in the functional characterization of this receptor. The benzamides used in these seminal studies were, in decreasing order of potency, cisapride (2), renzapride (3), zacopride (4), BRL 20627 (5) and the progenitor of the benzamide class metoclopramide (6). Whereas tropisetron and the benzamides played a pivotal role in establishing the existence of the 5-HT4 receptor, the utility of these drugs in the further characterization of the pharmacology of this receptor was severely limited by lack of selectivity. Tropisetron, renzapride and zacopride are high affinity 5-HT3 receptor antagonists,8 and cisapride and metodopramide have affinity for multiple receptor types.9 This chapter describes the significant progress made in the medicinal chemistry of 5-HT4 receptor ligands subsequent to the identification of these early leads which has resulted in the discovery of potent and selective 5-HT4 receptor agonists and antagonists, several of which are currently undergoing clinical evaluation. A previous review has admirably covered certain aspects of the medicinal chemistry of 5-HT4 receptor antagonists, most notably the structural relationships between 5-HT3 and 5-HT4 receptor antagonists.10