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.
Highlights
The transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel known as the Bcool receptor^ stemming from early work describing the cooling-activated current (Reid and Flonta 2001)
Single nucleotide polymorphs (SNPs) within the TRPM8 gene have consistently been found to show a protective association with migraine in multiple studies as well as in a meta-analysis of all migraine genome-wide association studies (GWAS) suggesting that TRPM8 modulators may act as migraine therapeutics (Chasman et al 2011; Schurks 2011; Freilinger et al 2012; Anttila et al 2013; Esserlind et al 2013; Chasman et al 2014)
AMG2850 acts as a potent and selective TRPM8 antagonists in vitro
Summary
The transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel known as the Bcool receptor^ stemming from early work describing the cooling-activated current (Reid and Flonta 2001). The localization of TRPM8 in subpopulations of small-diameter, cold-sensitive peripheral sensory neurons confirmed its activation by cool temperatures or compounds known to evoke cooling sensations such as menthol and icilin (McKemy et al 2002; Peier et al 2002; Nieto-Posadas et al 2011). TRPM8 KO mice do not show the normal warm temperature preference that is typical in mice (Dhaka et al 2006; Bautista et al 2007; Colburn et al 2007; Dhaka et al 2007; Knowlton et al 2010; Knowlton and McKemy 2011) nor do they show normal adaptive responses to cold or menthol-induced thermoregulatory challenges (Tajino et al 2007, 2011; Almeida et al 2012; Gavva et al 2012). Single nucleotide polymorphs (SNPs) within the TRPM8 gene have consistently been found to show a protective association with migraine in multiple studies as well as in a meta-analysis of all migraine GWAS suggesting that TRPM8 modulators may act as migraine therapeutics (Chasman et al 2011; Schurks 2011; Freilinger et al 2012; Anttila et al 2013; Esserlind et al 2013; Chasman et al 2014)
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