hCB1R ( IC50 = 0.3 nM ); GnRHR ( rCB1R = 0.4 nM ); hCB1R ( Ki = 0.13 nM ); rCB1R ( Ki = 0.27 nM )
Taranabant targets the cannabinoid-1 receptor (CB1R), a G protein-coupled receptor that is widely expressed in the central nervous system and peripheral tissues. CB1R is a key component of the endocannabinoid system and plays a central role in regulating appetite, food intake, and energy balance. Activation of CB1R by endogenous cannabinoids (endocannabinoids) stimulates appetite and promotes weight gain. Taranabant is a CB1 receptor inverse agonist that binds to the receptor and stabilizes it in an inactive conformation, thereby blocking the effects of endocannabinoids. The compound binds to human or rat CB1R with an IC50 of 0.3 and 0.4 nM, respectively, corresponding to Ki values of 0.13 and 0.27 nM. Taranabant also binds to human or rat CB2R with IC50 values of 290 and 470 nM, respectively, corresponding to Ki values of 170 and 310 nM, indicating selectivity for CB1 over CB2.

Taranabant (MK-0364) binds to CB1R in rats or humans with IC50 values of 0.3 and 0.4 nM, respectively.This results in Ki values of 0.13 and 0.27 nM, respectively. With IC50 values of 290 and 470 nM, respectively, and Ki values of 170 and 310 nM, respectively, taranabant binds to the human or rat CB2R. About 1000 times more selective than CB2R, CB1R has a higher selectivity ratio[1]. For the treatment of obesity, taranabant (MK-0364) is a novel acyclic cannabinoid-1 receptor inverse agonist. Taranabant's IC50 values for CB1R and CB2R by substituted amides are 0.3±0.1 nM and 290±60 nM, in that order. Taranabant is an inverse agonist of CB1R that has very little ability to bind proteins covalently. Taranabant is a CB1R inverse agonist that is incredibly strong and selective (900-fold over CB2), with an affinity that is more than 500 times higher than the original lead. Taranabant is found to be an inverse agonist (EC50=2.4±1.4 nM) in a functional assay of cyclic-AMP production[2].

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Taranabant demonstrates potent in vitro activity as a CB1 receptor inverse agonist. The compound binds to human CB1R with an IC50 of 0.3 nM (Ki = 0.13 nM) and to rat CB1R with an IC50 of 0.4 nM (Ki = 0.27 nM). Taranabant binds to human CB2R with an IC50 of 290 nM (Ki = 170 nM) and to rat CB2R with an IC50 of 470 nM (Ki = 310 nM), indicating approximately 1000-fold selectivity for CB1 over CB2. The compound's potent CB1 inverse agonist activity makes it a valuable tool for studying the role of the endocannabinoid system in appetite regulation, energy balance, and obesity. Taranabant has been evaluated in clinical trials for its anti-obesity effects.

In C57BL/6N mice, taranabant (MK-0364) inhibits food intake for two hours and overnight, as well as overnight weight gains. This effect is dose-dependent. Taranabant is found to significantly inhibit both 2-h and overnight food intake (36 and 69% reductions, respectively; P<0.05 and P<0.00001, respectively), as well as overnight body weight gains (48 and 165% reductions, respectively; P<0.01 and P<0.00001, respectively), at doses of 1 and 3 mg/kg (p.o.). In diet-induced obese (DIO) rats, taranabant has a dose-dependent effect that inhibits food intake and weight gain, with an acute minimum effective dose of 1 mg/kg[1]. In three species (dog, 0.2 mg/kg iv, 0.4 mg/kg po, F=31%; t_1/2=14 h; rhesus monkey, 0.2 mg/kg iv, 0.4 mg/kg po, F=31%, t_1/2=3.6 h), taranabant (MK-0364) exhibits a good pharmacokinetic profile. It also has good brain exposure (1 mg/kg iv, brain and plasma concentrations of 0.11 and 0.18 μM at 1 h, respectively).

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Taranabant has been evaluated in vivo for its anti-obesity effects in clinical trials. The compound was developed as an anti-obesity drug designed to block the effects of endocannabinoids, which stimulate appetite and promote weight gain. Taranabant has a maximum clinical trial phase of III (across all indications). Clinical trials evaluated the compound's ability to reduce body weight and food intake in obese patients. Despite demonstrating weight loss efficacy, Taranabant's development was discontinued due to safety concerns, including psychiatric side effects. The compound's in vivo effects on appetite and weight have been characterized in clinical studies. Detailed clinical trial data are available in the published literature.

In order to conduct the binding assay, different concentrations of Taranabant (MK-0364) are incubated with 0.5 nM [³H]CP 55,940, 1.5 μg of recombinant human CB1R-CHO membranes (or 0.1 μg of human CB2R-CHO membranes), 0.5 mg/mL fatty acid-free bovine serum albumin (BSA), 1× proteinase inhibitor mix, and 1% DMSO. Filtration is used to stop the reaction after a one-hour incubation period at 37°C. The filter plate is then washed to separate the bound from the free radioligand. Roughly 10% of the total added radiolabel is the total specifically bound radiolabel. Nonlinear curve fitting is used to determine the inhibitory IC50 values, from which Ki values are derived. In the recombinant human CB1R-CHO membranes, the CB1R density (B_max=5 pmol/mg based on [³H]CP 55,940 binding) is comparable to that found in rat brain membranes (3-5 pmol/mg)[1].

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The in vitro receptor binding assay for Taranabant measures the compound's affinity for the CB1 and CB2 receptors. Membrane preparations from cells expressing human or rat CB1 or CB2 receptors are incubated with varying concentrations of Taranabant (typically ranging from picomolar to micromolar) in the presence of a radiolabeled cannabinoid receptor ligand. The amount of bound radioligand is measured by scintillation counting, and IC50 and Ki values are determined by fitting competition binding curves. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations. Selectivity is assessed by testing the compound against other cannabinoid receptors and related targets. Appropriate positive controls (known CB1 antagonists) and negative controls (DMSO vehicle) are included in each assay run.

The in vitro functional assay for Taranabant measures the compound's inverse agonist activity at the CB1 receptor. Cells expressing the CB1 receptor are treated with varying concentrations of Taranabant or vehicle control (DMSO). CB1 receptor activity is measured by assessing downstream signaling events such as inhibition of cAMP accumulation (CB1 is a Gi-coupled receptor that inhibits adenylyl cyclase). The inverse agonist activity of Taranabant is quantified by measuring the increase in cAMP levels (reversal of basal Gi-mediated inhibition) or by measuring the inhibition of agonist-induced signaling. The compound's potency and efficacy as an inverse agonist are determined by fitting dose-response curves. The compound's selectivity for CB1 over CB2 is assessed in similar assays using cells expressing CB2.

Mice: The mice used are male C57BL/6N wild-type mice. For oral administration to mice later on, MK-0364 is dissolved or dispersed (by sonication) as a fine, homogenous suspension in 0.225% methylcellulose/10% Tween 80 in water. After weighing each mouse, male mice (n = 12 per group, age 23 weeks, mean body weight 34.14±0.53 g) are given either vehicle (0.225% methylcellulose/10% Tween 80 in water) or Taranabant (1 or 3 mg/kg) by oral gavage, about 30 minutes before the start of the dark phase of the light cycle. After dosing, mice are fed unlimited amounts during the dark phase. Five minutes prior to the start of the dark phase of the light cycle, a preweighed aliquot of a very appetizing medium-high fat diet (25% kcal from sucrose, 32% kcal from fat, 4.41 kcal/g) is placed in the cage's food hopper. It is then weighed two and eighteen hours later. In addition, all mice are weighed 18 h after the onset of the dark phase of the light cycle. In this crossover design study, the vehicle and 1-mk/kg groups receive their doses first. Following a four-day washout period, 3 mg/kg of taranabant is administered to the previous vehicle group, while the previous 1-mg/kg group receives a vehicle dose. Rats: Male Sprague-Dawley DIO rats are randomly assigned to groups (n=6 rats/group) for the purpose of administering compound and vehicle doses in acute experiments. To ascertain the impact on overnight body weight gain, rats are weighed 17 hours after dosing. Oral taraditabant at 0.3, 1, and 3 mg/kg p.o. is given to DIO rats one hour prior to the onset of the dark cycle at 3:00 PM. 10% Tween 80 in water is the vehicle, and 2 mL/kg is the dosage volume. Over the course of eighteen hours, powdered food is served in food cups that are continuously weighed at 5-minute intervals. A computerized system is used to record the data.

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In vivo animal experiments with Taranabant were conducted during its preclinical and clinical development. The compound was administered orally in animal models and clinical trials. In preclinical studies, Taranabant's effects on food intake, body weight, and metabolic parameters were assessed in rodent models of obesity. In clinical trials, the compound was evaluated for its effects on weight loss, appetite, and safety in obese patients. Taranabant has a maximum clinical trial phase of III. Despite demonstrating weight loss efficacy, the compound's development was discontinued. Detailed experimental protocols, including dosing regimens and endpoints, are described in the primary literature and clinical trial reports.

Detailed pharmacokinetic (PK) parameters for Taranabant are partially documented from clinical studies. The compound is orally bioavailable. Taranabant has a molecular weight of 515.96 and a chemical formula of C27H25ClF3N3O2. The compound should be stored long-term in a cool, dry place. The compound is soluble in DMSO for formulation purposes. For in vivo oral administration, Taranabant was typically formulated using appropriate vehicles to ensure adequate solubility and stability. Detailed PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are available in the primary literature and clinical trial reports and should be consulted for specific experimental planning.

Comprehensive toxicological data for Taranabant are available from preclinical and clinical studies. The compound's development as an anti-obesity drug was discontinued due to safety concerns, including psychiatric side effects observed in clinical trials. As a research-grade compound, Taranabant is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation. Toxicological data from clinical studies are available in the published literature and should be consulted for safety information.

[1]. 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 Ther . 2007 Jun;321(3):1013-22.

[2]. 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 Med Chem . 2006 Dec 28;49(26):7584-7.

Taranabant is a stilbene compound.

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Drug Indications
It has been studied for the treatment of obesity.
Obesity

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Taranabant is a research compound developed for studying the role of the endocannabinoid system and CB1 receptors in appetite regulation, energy balance, and obesity. The compound is a potent CB1 receptor inverse agonist with IC50 values of 0.3 nM for human CB1 and 0.4 nM for rat CB1, and approximately 1000-fold selectivity over CB2. Taranabant was developed as an anti-obesity drug and reached Phase III clinical trials but was discontinued due to safety concerns. Despite its clinical discontinuation, Taranabant remains a valuable tool for studying CB1 receptor pharmacology and the endocannabinoid system. Taranabant is available from various chemical suppliers for research purposes.

C27H25CLF3N3O2

515.9545

515.159

C, 62.85; H, 4.88; Cl, 6.87; F, 11.05; N, 8.14; O, 6.20

701977-09-5

Taranabant racemate; 701977-00-6; Taranabant ((1R,2R)stereoisomer); 701977-08-4

11226090

White to off-white solid powder

1.3

634.2ºC at 760 mmHg

6.704

1

7

8

36

776

2

ClC1=CC=C(C[C@@H](C2=CC=CC(C#N)=C2)[C@@H](NC(C(C)(OC3=CC=C(C=N3)C(F)(F)F)C)=O)C)C=C1

QLYKJCMUNUWAGO-GAJHUEQPSA-N

InChI=1S/C27H25ClF3N3O2/c1-17(34-25(35)26(2,3)36-24-12-9-21(16-33-24)27(29,30)31)23(14-18-7-10-22(28)11-8-18)20-6-4-5-19(13-20)15-32/h4-13,16-17,23H,14H2,1-3H3,(H,34,35)/t17-,23+/m0/s1

N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]oxypropanamide

MK-0364; MK 0364; MK0364

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 42 mg/mL (~81.4 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)