AMG2850, a potent and selective TRPM8 antagonist, is not effective in rat models of inflammatory mechanical hypersensitivity and neuropathic tactile allodynia.
Naunyn Schmiedebergs Arch Pharmacol, 2015/4;388(4):465-76.
Lehto SG[1], Weyer AD, Zhang M, Youngblood BD, Wang J, Wang W, Kerstein PC, Davis C, Wild KD, Stucky CL, Gavva NR
Affiliations
PMID: 25662185DOI: 10.1007/s00210-015-1090-9
Impact factor: 3.195
Abstract
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.
MeSH terms
Action Potentials; Animals; Behavior, Animal; Blood Pressure; Brain; CHO Cells; Calcium; Cold Temperature; Cricetinae; Cricetulus; Freund's Adjuvant; Humans; Hyperalgesia; Male; Menthol; Mice, Inbred C57BL; Naphthyridines; Pain; Pyrimidinones; Rats; Rats, Sprague-Dawley; Sciatic Nerve; TRPM Cation Channels
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