In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening

Iraci, N.; Ostacolo, C.; Medina-Peris, A.; Ciaglia, T.; Novoselov, A.M.; Altieri, A.; Cabañero, D.; Fernandez-Carvajal, A.; Campiglia, P.; Gomez-Monterrey, I.; Bertamino, A.; Kurkin, A.V.

Авторы: Iraci Nunzio, Ostacolo Carmine, Medina-Peris Alicia, Ciaglia Tania, Novoselov Anton M., Altieri Andrea, Cabañero David, Fernandez-Carvajal Asia, Campiglia Pietro, Gomez-Monterrey Isabel, Bertamino Alessia, Kurkin Alexander V.
Журнал: International Journal of Molecular Sciences
Том: 23
Год издания: 2022
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 2070
DOI: 10.3390/ijms23042070
Аннотация: Transient receptor potential melastatin type 8 (TRPM8) is a target for the treatment ofdifferent physio-pathological processes. While TRPM8 antagonists are reported as potential drugs forpain, cancer, and inflammation, to date only a limited number of chemotypes have been investigatedand thus a limited number of compounds have reached clinical trials. Hence there is high value insearching for new TRPM8 antagonistic to broaden clues to structure-activity relationships, improvepharmacological properties and explore underlying molecular mechanisms. To address this, theEDASA Scientific in-house molecular library has been screened in silico, leading to identifyingtwenty-one potentially antagonist compounds of TRPM8. Calcium fluorometric assays were used tovalidate the in-silico hypothesis and assess compound selectivity. Four compounds were identified as selective TRPM8 antagonists, of which two were dual-acting TRPM8/TRPV1 modulators. The most potent TRPM8 antagonists (BB 0322703 and BB 0322720) underwent molecular modelling studiesto highlight key structural features responsible for drug–protein interaction. The two compoundswere also investigated by patch-clamp assays, confirming low micromolar potencies. The mostpotent compound (BB 0322703, IC50 1.25 0.26 M) was then profiled in vivo in a cold allodinyamodel, showing pharmacological efficacy at 30 M dose. The new chemotypes identified showedremarkable pharmacological properties paving the way to further investigations for drug discoveryand pharmacological purposes.
Добавил в систему: Куркин Александр Витальевич

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In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screeningстатья

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