A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats.

Abstract

The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 micromol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 micromol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.

• Authors: Prisca Honore, Carol T Wismer, Joe Mikusa, Chang Z Zhu, Chengmin Zhong, Donna M Gauvin, Arthur Gomtsyan, Rachid El Kouhen, Chih-Hung Lee, Kennan Marsh, James P Sullivan, Connie R Faltynek, Michael F Jarvis
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 314 Issue 1 Pg. 410-21 (Jul 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15837818 (Publication Type: Journal Article)

Chemical References

• 1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea
• Analgesics
• Isoquinolines
• Receptors, Drug
• Formaldehyde
• Urea
• Carrageenan
• Freund's Adjuvant
• Capsaicin

Topics

• Acute Disease
• Analgesics
• Animals
• Capsaicin
• Carrageenan
• Chronic Disease
• Dose-Response Relationship, Drug
• Edema (chemically induced, complications)
• Formaldehyde
• Freund's Adjuvant
• Hot Temperature
• Hyperalgesia (chemically induced, drug therapy)
• Inflammation (complications)
• Isoquinolines (pharmacology)
• Ligation
• Male
• Motor Activity (drug effects)
• Osteoarthritis (complications)
• Pain (drug therapy, etiology)
• Pain Measurement (drug effects)
• Pain, Postoperative (drug therapy)
• Postural Balance (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Drug (antagonists & inhibitors)
• Sciatic Nerve (pathology)
• Spinal Nerves (pathology)
• Urea (analogs & derivatives, pharmacology)