PubMed 25662185

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: TRP , TRPA , TRPA1 , TRPM , TRPM8 , TRPV , TRPV1

Title: AMG2850, a potent and selective TRPM8 antagonist, is not effective in rat models of inflammatory mechanical hypersensitivity and neuropathic tactile allodynia.

Authors: Sonya G Lehto, Andy D Weyer, Maosheng Zhang, Beth D Youngblood, Judy Wang, Weiya Wang, Patrick C Kerstein, Carl Davis, Kenneth D Wild, Cheryl L Stucky, Narender R Gavva

Journal, date & volume: Naunyn Schmiedebergs Arch. Pharmacol., 2015 Apr , 388, 465-76

PubMed link:

TRPM8 has been implicated in pain and migraine based on dorsal root- and trigeminal ganglion-enriched expression, upregulation in preclinical models of pain, knockout mouse studies, and human genetics. Here, we evaluated the therapeutic potential in pain of AMG2850 ((R)-8-(4-(trifluoromethyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxamide), a small molecule antagonist of TRPM8 by in vitro and in vivo characterization. AMG2850 is potent in vitro at rat TRPM8 (IC90 against icilin activation of 204 ± 28 nM), highly selective (>100-fold IC90 over TRPV1 and TRPA1 channels), and orally bioavailable (F po > 40 %). When tested in a skin-nerve preparation, AMG2850 blocked menthol-induced action potentials but not mechanical activation in C fibers. AMG2850 exhibited significant target coverage in vivo in a TRPM8-mediated icilin-induced wet-dog shake (WDS) model in rats (at 10 mg/kg p.o.). However, AMG2850 did not produce a significant therapeutic effect in rat models of inflammatory mechanical hypersensitivity or neuropathic tactile allodynia at doses up to 100 mg/kg. The lack of efficacy suggests that either TRPM8 does not play a role in mediating pain in these models or that a higher level of target coverage is required. The potential of TRPM8 antagonists as migraine therapeutics is yet to be determined.