Cannabinoid receptor type 1 inverse agonist
CAS：701977-09-5
分子式：C27H25ClF3N3O2
分子量：515.97
纯度：98%
存储：Store at -20°C

Background:

Taranabant is a highly potent and selective cannabinoid 1 (CB1) receptor inverse agonist that inhibits the binding and functional activity of various agonists, with a binding Ki of 0.13 nM for the human CB1R in vitro.

Taranabant (MK-0364) binds to human or rat CB1R with an IC50 of 0.3 and 0.4 nM, respectively, corresponding to a Ki value of 0.13 and 0.27 nM, respectively. Taranabant binds to the human or rat CB2R with an IC50 value of 290 and 470 nM, respectively, corresponding to a Ki value of 170 and 310 nM, respectively. The selectivity ratio of CB1R over CB2R is approximately 1000-fold[1]. Taranabant (MK-0364) is a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. IC50s of Taranabant for CB1R and CB2R by substituted amides is 0.3±0.1 nM, and 290±60 nM, respectively. Taranabant is a CB1R inverse agonist with minimal potential for covalent protein binding. Taranabant is an exceptionally potent and selective (900-fold over CB2) CB1R inverse agonist with >500-fold improvement in affinity over the original lead. In a functional assay of cyclic-AMP production, Taranabant is determined to be an inverse agonist (EC50=2.4±1.4 nM)[2].

Taranabant (MK-0364) dose-dependently inhibits 2 h and overnight food intake as well as overnight gains in body weight in C57BL/6N mice. At the 1- and 3-mg/kg doses (p.o.), Taranabant significantly inhibits 2-h food intake (36 and 69% reductions, respectively; P<0.05 and P<0.00001, respectively) and overnight food intake (13 and 40% reductions, respectively; P<0.05 and P<0.00001, respectively) as well as overnight gains in body weight (48 and 165% reductions, respectively; P<0.01 and P<0.00001, respectively). Taranabant dose-dependently inhibits food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats[1]. Taranabant (MK-0364) has a good pharmacokinetic profile in three species (rat, 1 mg/kg iv, 2 mg/kg po, F=74%, t1/2=2.7 h; dog, 0.2 mg/kg iv, 0.4 mg/kg po, F=31%; t1/2=14 h; rhesus monkey, 0.2 mg/kg iv, 0.4 mg/kg po, F=31%, t1/2=3.6 h) and good brain exposure (1 mg/kg iv, brain and plasma concentrations of 0.11 and 0.18 μM at 1 h, respectively)[2].

参考文献:
[1]. Fong TM, et al. Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents. J Pharmacol Exp T
[2]. Lin LS, et al. Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J M