Arylcarbamate derivatives of 1-piperidineethanol as potent ligands for 5-HT4 receptors.
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).
Soulier
J L
JL
CNRS-BIOCIS, URA 1843, Faculté de Pharmacie, Chåtenay-Malabry, France.
Yang
D
D
Brémont
B
B
Croci
T
T
Guzzi
U
U
Langlois
M
M
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D003342:Corpus Striatum / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D009197:Myenteric Plexus / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship
D002219:Carbamates; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4