TRPM8, often referred to as the cold receptor, is a polymodal nociceptor of the somatosensory nervous system and a major sensor of cold nociception in humans. TRPM8 antagonists have been explored as pharmacotherapies for cold hypersensitivity in neuropathic pain, and migraine, among others; while paradoxically both TRPM8 agonists and antagonists are reported to induce anti-nociception in models of neuropathic pain. We conducted molecular dynamics (MD) simulations of known antagonists in our human homology model based on the avian cryo-EM structure TRPM8FA (PDB 6BPQ, ~4.1 Å) to guide our structure-based design of novel TRPM8 chemical probes and therapeutic scaffolds based on the cognate ligand (−)-menthol with an antagonist profile, as these chemotypes are currently lacking in the literature. Using this approach, we will report the discovery of a novel biphenyl amide series with potent TRPM8 antagonist activity at human TRPM8. Spiro[4.5]decan-8-yl analog 14 (hTRPM8 IC50: 2.4 ± 1.0 nM) dose dependently blocks icilin-triggered shaking behaviors in mice. When administered locally, analog 14 dose dependently inhibits cold allodynia evoked by the chemotherapy oxaliplatin in a murine model of peripheral neuropathy at sub microgram doses. Our results suggest that these scaffolds can find utility as potent antagonist chemical probes derived from (−)-menthol, as well as small molecule therapies for chemotherapy-induced peripheral neuropathy (CIPN) and other sensory neuropathies.

Structure-based design of novel biphenyl amide antagonists of human transient receptor potential cation channel subfamily M member 8 channels (TRPM8)

ACS Fall 2020 Virtual Meeting

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