a-784168 and arachidonyl-dopamine

A series of 1,2,3,6-tetrahydropyridyl-4-carboxamides, exemplified by 6, have been synthesized and evaluated for in vitro TRPV1 antagonist activity, and in vivo analgesic activity in animal pain models. The tetrahydropyridine 6 is a novel TRPV1 receptor antagonist that potently inhibits receptor-mediated Ca2+ influx in vitro induced by several agonists, including capsaicin, N-arachidonoyldopamine (NADA), and low pH. This compound penetrates the CNS and shows potent anti-nociceptive effects in a broad range of animal pain models upon oral dosing due in part to its ability to antagonize both central and peripheral TRPV1 receptors. The SAR leading to the discovery of 6 is presented in this report.

Topics: Administration, Oral; Analgesics; Animals; Arachidonic Acids; Calcium; Capsaicin; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Hyperalgesia; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; TRPV Cation Channels