Arylcarbamate Derivatives of 1-Piperidineethanol as Potent Ligands for 5-HT₄Receptors

Abstract

A series of carbamate derivatives (7) of 2-(1-piperidinyl)ethyl 4-amino-5-chloro-2-methoxybenzoates, which have been described as potent agonists and antagonists of 5-HT4 receptors, were synthesized. They were evaluated using radioligand binding assays with [3H]GR 113808, a 5-HT4 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 inactive 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 (Ki = 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 favorable (Ki = 1.1 +/- 0.6 nM for both isomers). 8c is an antagonist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1).

A Rationally Designed Prototype of a Molecular Motor

“…Accordingly, carbamate formation via isocyanate was chosen. The procedure for the formation of isocyanates from amines was adapted from a protocol reported by Soulier et al In model studies with triptycene amine 57 it was found that use of five equivalents of triethylamine allowed for complete and rapid formation of isocyanate 60 without accumulation of 58 and/or 59 (Scheme ). The excess base also aided in the formation of carbamate 62 in these studies.…”

5‐HT4 Receptor Ligands: Applications and New Prospects

“…The presence of the ester function is an important drawback for the administration in vivo of the compounds due to their putative short half-lives. A series of carbamates 66 derived from the previous esters were prepared (Scheme 7). Conversely to the esters where the presence of the 4-amino-5-chloro substituents was mandatory to obtain active compounds, the oalkoxyphenyl carbamates 10 were the most potent and characterised as 5-HT4 receptor antagonist in the guinea-pig ileum.…”

5-HT4Receptor Ligands: Applications and New Prospects

“…The presence of the ester function is a significant drawback for the administration in vivo of the compounds because of their putative short half-lives. A series of carbamates derived from the previous esters were prepared (Chart ). In contrast to the esters where the presence of the 4-amino-5-chloro substituents was mandatory for obtaining active compounds, the o -alkoxyphenyl carbamates 10 were the most potent and were characterized as a 5-HT 4 receptor antagonist in the guinea pig ileum.…”