(-)-Menthylamine derivatives as potent and selective antagonists of transient receptor potential melastatin type-8 (TRPM8) channels.
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.
Ortar
Giorgio
G
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy. giorgio.ortar@uniroma1.it
De Petrocellis
Luciano
L
Morera
Ludovica
L
Moriello
Aniello Schiano
AS
Orlando
Pierangelo
P
Morera
Enrico
E
Nalli
Marianna
M
Di Marzo
Vincenzo
V
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
D000970:Antineoplastic Agents; D050053:TRPM Cation Channels; D008610:Menthol; D053148:Caspase 3; D053179:Caspase 7