NEW ESTERS OF 4-AMINO-5-CHLORO-2-METHOXYBENZOIC ACID AS POTENT AGONISTS AND ANTAGONISTS FOR 5-HT4 RECEPTORS

A number of benzoates derived from 4-amino-5-chloro-2-methoxybenzoic a cid and substituted 1-piperidineethanol were synthesized and found to be potent 5-HT4 receptor agonists in the electrically-stimulated myent eric plexus and longitudinal muscle of the guinea pig ileum and the ra t esophagus muscle. Monosubstitution of the piperidine ring with Me, O H, NH-Ac, or CONH2 groups gave compounds equipotent to 7a (ML 10302), a 5-HT4 receptor agonist previously reported to have nanomolar affinit y. 7a,k were as potent as serotonin (5-HT) but had maximal responses w hich were only 60-80% of that of 5-HT, suggesting a partial agonist pr ofile for these compounds. Binding assays were performed with [H-3]GR 113808 in the rat striatum, and several of these compounds were found to have nanomolar affinity for 5-HT4 receptors (7a, K-i = 1.07 +/- 0.5 nM; 7k, K-i = 1.0 +/- 0.3 nM). The introduction of two methyl groups on the piperidine ring brought about a dramatic change in the pharmaco logical profile of 2-[(cis- and ridinyl)ethyl]-4-amino-5-chloro-2-meth oxybenzoate, 7g,h. 7g (Ki = 0.26 +/- 0.06 nM) inhibited the relaxant a ction of 5-HT in the rat esophagus muscle with a pA(2) value of 8.6. T he advantage of the ester function was demonstrated by comparing the a ctivity of several such compounds at 5-HT4 receptors with those of the corresponding amidic derivatives. This difference was less marked whe n the basic moiety was sterically constrained as in the quinuclidine a nd tropane moieties. Structural analyses of 7a,g were performed by det ermining their X-ray crystal structures and by molecular modelling (SY BYL). A relatively limited number of minimum energy conformers was fou nd for both compounds. They were characterized by the cis folded confo rmation of the ethyl chain and by the orientation of the lone pair of the nitrogen atom pointing out of the molecule as seen in conformation ally-constrained benzamides such as zacopride and renzapride. A hypoth etical model for the 5-HT4 receptor with two sites for the binding of agonist and antagonist molecules was proposed.