Tetrahydropyridine-4-carboxamides as novel, potent transient receptor potential vanilloid 1 (TRPV1) antagonists.

Abstract

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.

• Authors: Brian S Brown, Ryan Keddy, Guo Zhu Zheng, Robert G Schmidt, John R Koenig, Heath A McDonald, Bruce R Bianchi, Prisca Honore, Michael F Jarvis, Carol S Surowy, James S Polakowski, Kennan C Marsh, Connie R Faltynek, Chih-Hung Lee
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 18 Pg. 8516-25 (Sep 15 2008) ISSN: 1464-3391 [Electronic] England
• PMID: 18722778 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Arachidonic Acids
• Pyridines
• TRPV Cation Channels
• TRPV1 receptor
• arachidonyl dopamine
• Capsaicin
• Calcium
• Dopamine

Topics

• Administration, Oral
• Analgesics (chemical synthesis, pharmacology)
• Animals
• Arachidonic Acids (pharmacology)
• Calcium (metabolism)
• Capsaicin (pharmacology)
• Disease Models, Animal
• Dopamine (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Hydrogen-Ion Concentration
• Hyperalgesia (drug therapy, metabolism, pathology)
• Pain Measurement
• Pyridines (administration & dosage, chemical synthesis, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• TRPV Cation Channels (antagonists & inhibitors, metabolism)