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

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...

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Detalles Bibliográficos
Autores: Fernandez-Carvajal, Asia, BERTAMINO, Alessia, Ostacolo, Carmine, Medina Peris, Alicia, Di Sarno, Veronica, Lauro, Gianluigi, Ciaglia, Tania, Vestuto, Vincenzo, Di Giacomo Pepe , Giuseppe, Basilicata, Manuela Giovanna, Musella, Simona, Smaldone, Gerardina, Cristiano, Claudia, González-Rodríguez, Sara, Bifulco, Giuseppe, Campiglia, Pietro, Gomez Monterrey, Isabel Maria, Russo, Roberto
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Miguel Hernández de Elche
Repositorio:REDIUMH. Depósito Digital de la UMH
OAI Identifier:oai:dspace.umh.es:11000/34367
Acceso en línea:https://hdl.handle.net/11000/34367
Access Level:acceso abierto
Palabra clave:Antagonists
Molecular structure
Reaction products
Screening assays
Substituents
CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica
Descripción
Sumario: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.

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