Correlation Engine 2.0
Clear Search sequence regions

Sizes of these terms reflect their relevance to your search.

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.


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

Expand section icon Mesh Tags

Expand section icon Substances

PMID: 32787109

View Full Text