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Transient receptor potential melastatin 8 (TRPM8) ion channel represents a valuable pharmacological option for several therapeutic areas. Here, a series of conformationally restricted derivatives of the previously described TRPM8 antagonist N , N '-dibenzyl tryptophan 4 were prepared and characterized in vitro by Ca 2+ -imaging and patch-clamp electrophysiology assays. Molecular modeling studies led to identification of a broad and well-defined interaction network of these derivatives inside the TRPM8 binding site, underlying their antagonist activity. The (5 R ,11a S )-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1 H -imidazo[1',5':1,6]pyrido[3,4- b ]indole-1,3(2 H )-dione ( 31a ) emerged as a potent (IC 50 = 4.10 ± 1.2 nM), selective, and metabolically stable TRPM8 antagonist. In vivo, 31a showed significant target coverage in an icilin-induced WDS (at 11.5 mg/kg ip), an oxaliplatin-induced cold allodynia (at 10-30 μg sc), and CCI-induced thermal hyperalgesia (at 11.5 mg/kg ip) mice models. These results confirm the tryptophan moiety as a solid pharmacophore template for the design of highly potent modulators of TRPM8-mediated activities.

Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities