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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 Ca2+-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 (5R,11aS)-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione (31a) emerged as a potent (IC50 = 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.

Citation

Alessia Bertamino, Carmine Ostacolo, Alicia Medina, Veronica Di Sarno, Gianluigi Lauro, Tania Ciaglia, Vincenzo Vestuto, Giacomo Pepe, Manuela Giovanna Basilicata, Simona Musella, Gerardina Smaldone, Claudia Cristiano, Sara Gonzalez-Rodriguez, Asia Fernandez-Carvajal, Giuseppe Bifulco, Pietro Campiglia, Isabel Gomez-Monterrey, Roberto Russo. Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities. Journal of medicinal chemistry. 2020 Sep 10;63(17):9672-9694

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PMID: 32787109

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