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

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

来源：Naunyn-Schmiedebergs Archives of Pharmacology, 2015, 388(4): 465-476.

DOI：10.1007/s00210-015-1090-9

• TRPM8
• AMG2850
• Pain
• Inflammatory
• Neuropathic
• Hypersensitivity
• Small molecule
• Therapeutic
• Rat

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.

• 出版日期2015-4