title: Identification of Indole Alkaloid Structural Units Important for Stimulus-Selective TRPM8 Inhibition: SAR Study of Naturally Occurring Iboga Derivatives.
abstract: The iboga alkaloid voacangine (1) has been reported previously to be the first stimulus-selective TRPM8 antagonist. In the present report, a structure-activity relationship (SAR) study is described on the effects of some naturally occurring indole alkaloid analogues on TRPM8 inhibition. Dihydrocatharanthine (10) and catharanthine (11) were found to be inhibitors of TRPM8 activity, and their IC50 values were equivalent to that of BCTC, a potent and representative TRPM8 antagonist. Furthermore, it was shown that the iboga moiety is the most crucial unit for TRPM8 blockade and that its stereostructure, as found in 1 but not in 10 and 11, is essential for chemical agonist-selective TRPM8 inhibition. These findings should provide useful information for synthesizing additional stimulus-selective and TRPM8-selective blockers.
authors: Graduate School of Nutritional and Environmental Sciences, University of Shizuoka , 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors: Yuko
authors: Y
authors: Terada
authors: Department of Biofunctional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Mariko
authors: M
authors: Kitajima
authors: Department of Biofunctional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Fuyumi
authors: F
authors: Taguchi
authors: Department of Biofunctional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Hiromitsu
authors: H
authors: Takayama
authors: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University , 1 Gumyo, Togane, Chiba 283-8555, Japan.
authors: Syunji
authors: S
authors: Horie
authors: Graduate School of Nutritional and Environmental Sciences, University of Shizuoka , 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors: Tatsuo
authors: T
authors: Watanabe
mesh_terms: D007050:Ibogaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors*; D030014:Tabernaemontana / Q000737:chemistry*
chemical_list: D026121:Indole Alkaloids; D011719:Pyrazines; D011725:Pyridines; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D007050:Ibogaine; C012098:voacangine