ARYLCARBAMATE DERIVATIVES OF 1-PIPERIDINEETHANOL AS POTENT LIGANDS FOR 5-HT4 RECEPTORS

A series of carbamate derivatives (7) of 2-(1-piperidinyl)ethyl 4-amin o-5-chloro-2-methoxybenzoates, which have been described as potent ago nists and antagonists of 5-HT4 receptors, were synthesized. They were evaluated using radioligand binding assays with [H-3]GR 113808, a 5-HT 4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig. In contrast to the previously described ester derivatives, a drop in the affinity for 5-HT4 receptors was observed and the compounds were inact ive as agonists in the guinea pig ileum preparation. Unexpectedly, the ortho-substituted carbamates 8b,c (R' = H, RO = MeO or EtO, R '' = H) had nanomolar affinity for 5-HT4 receptors (K-i = 8.9 +/- 0.5 and 2.6 +/- 0.4 nM, respectively). As reported previously, the cis- or trans- 3,5-dimethyl substitution of piperidine (8n,o) was particularly favora ble (K-i = 1.1 +/- 0.6 nM for both isomers). 8c is an antagonist equip otent to the 5-HT4 receptor antagonist SDZ 205-557 (1).