title: (-)-Menthylamine derivatives as potent and selective antagonists of transient receptor potential melastatin type-8 (TRPM8) channels.
abstract: A series of twenty-two (-)-menthylamine derivatives was synthesized and tested on TRPM8, TRPV1, and TRPA1 channels. Five of the novel compounds, that is, 1d, 1f, 2b, 2c, and 2e behaved as potent TRPM8 antagonists with IC(50) values versus icilin and (-)-menthol between 20 nM and 0.7 microM, and were between 4- and approximately 150-fold selective versus TRPV1 and TRPA1 activation. Compound 1d also induced caspase 3/7 release in TRPM8-expressing LNCaP prostate carcinoma cells, but not in non-TRPM8 expressing DU-145 cells. Five other derivatives, that is, 1a, 1g, 1h, 2f, and 2h were slightly less potent than previous compounds but still relatively selective versus TRPV1 and TRPA1.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy. giorgio.ortar@uniroma1.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ortar
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Ludovica
authors.initials: L
authors.lastname: Morera
authors.forename: Aniello Schiano
authors.initials: AS
authors.lastname: Moriello
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.forename: Enrico
authors.initials: E
authors.lastname: Morera
authors.forename: Marianna
authors.initials: M
authors.lastname: Nalli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008610:Menthol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050053:TRPM Cation Channels; D008610:Menthol; D053148:Caspase 3; D053179:Caspase 7