CB1/cannabinoid receptor 1

TM38837 (10-100 mg/kg; oral) significantly increases freezing behavior at the 100 mg/kg dose [1].

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Rimonabant was the first selective CB1 antagonist/inverse agonist introduced into clinical practice to treat obesity and metabolic-related disorders. It was withdrawn from market due to the notably increased rates of psychiatric side effects. We have evaluated TM38837, a novel, largely peripherally restricted CB1 antagonist, in terms of fear-promoting consequences of systemic vs. intracerebral injections. Different groups of male C57BL/6 N mice underwent auditory fear conditioning, followed by re-exposure to the tone. Mice were treated per os (p.o.) with TM38837 (10, 30, or 100 mg/kg), rimonabant (10 mg/kg; a brain penetrating CB1 antagonist/inverse agonist which served as a positive control), or vehicle, 2 h prior the tone presentation. Only the high dose of TM38837 (100 mg/kg) induced a significant increase in freezing behavior, similar to that induced by rimonabant (10 mg/kg) (p < 0.001). If injected into the brain both TM38837 (10 or 30 μg/mouse) and rimonabant (1 or 10 μg/mouse) caused a sustained fear response to the tone, which was more pronounced after rimonabant treatment. Taken together, TM38837 was at least one order of magnitude less effective in promoting fear responses than rimonabant. Given the equipotency of the two CB1 antagonists with regard to weight loss and metabolic syndrome-like symptoms in rodent obesity models, our results point to a critical dose range in which TM3887 might be beneficial for indications such as obesity and metabolic disorders with limited risk of fear-promoting effects. [1]

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The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [-26.70% [90% confidence interval (CI) -40.9, -12.6%]; -7.10%, (90%CI -18.1, 5.3%); -7.30%, (90% CI -11.5%, -3.0%) respectively] and TM38837 500 mg [-22.10% (90% CI -34.9, -9.4%); -12.20% (90% CI -21.6%, -1.7%); -8.90% (90% CI -12.8%, -5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions: Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.[2]

Animal/Disease Models: 7-8 weeks old male C57BL/6 N mice (B6N)[1]
Doses: 10, 30 or 100 mg/kg
Route of Administration: Oral
Experimental Results: High dose (100 mg/kg) induced significant freezing Increase behavior.

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Aim: Cannabinoid receptor type 1 (CB1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM-38837 was studied in humans. Methods: This was a double-blind, randomized, placebo-controlled, crossover study. On occasions 1-4, 24 healthy subjects received 5 × 4 mg THC with TM-38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK-PD modelling.[2]

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Drugs and Experimental Design [1]
Two different experiments were performed. In Experiment 1, rimonabant (Kd~0.61 nM; Rinaldi-Carmona et al., 1996) (RIM: 10 mg/kg), TM-38837 (Kd~16 nM; Noerregaard et al., 2010) (10, 30, or 100 mg/kg, 7TM PHARMA), or vehicle (VHC: 0.1% Tween 80 and 1% hydroxypropyl methylcellulose) were administered per os (p.o.) in a volume of 5 ml/kg, 2 h prior the tone re-exposure (days 1–3). On day 10, all the mice were treated with vehicle (VHC) 2 h prior the exposure to a 3-min tone. The dose of rimonabant (10 mg/kg) was selected based on a dose-response curves experiment, where an additional group of mice was treated with rimonabant (RIM 3 mg/kg, s.c.) as a positive control, 1 h prior to exposure to the 3-min tone. On day 11, four groups of mice (n = 5–6 per group) were treated with TM38837 (TM: 10, 30 or 100 mg/kg, p.o.) or rimonabant (RIM: 10 mg/kg, p.o.) and, 2 h later, were decapitated after short isoflurane anesthesia, and trunk blood was collected in pre-chilled EDTA tubes. The samples were centrifuged at 1500 g for 10 min at 4°C. The entire resultant plasma obtained was transferred to suitably labeled polypropylene tubes and stored upright at −20°C for subsequent measurement of plasma levels. [1]
In Experiment 2, rimonabant and TM-38837 were dissolved in vehicle solution (10% DMSO and 10% Cremophor EL in saline). The compounds were administered intracerebroventricularly (icv) in a volume of 2.0 μl/mouse. Different groups of mice were treated icv with TM38837 (TM: 10 or 30 μg/mouse), rimonabant (RIM: 1 μg/mouse), or vehicle (VHC) 30 min prior to re-exposure to the tone (days 1–3). On day 10, all mice were treated with vehicle (VHC) 30 min prior the tone re-exposure. The dose of rimonabant (1 μg/mouse) was selected on the basis of a dose-response experiment. For all groups, injections were given under light isoflurane anesthesia to avoid differences in coping with the stressful injection procedure. The injection cannula protruded the guide cannula by 1 mm.

[1]. The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows ReducedFear-Promoting Effects in Mice. Front Pharmacol. 2019 Mar 20;10:207.

[2]. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br J Clin Pharmacol. 2013 Dec;76(6):846-57.

1-(2,4-dichlorophenyl)-4-ethyl-N-piperidin-1-yl-5-[5-[2-[4-(trifluoromethyl)phenyl]ethynyl]thiophen-2-yl]pyrazole-3-carboxamide has been reported in Cordyceps militaris, Aspergillus, and Chrysothamnus viscidiflorus with data available.

C30H25CL2F3N4OS

617.5122

616.107

C, 58.35; H, 4.08; Cl, 11.48; F, 9.23; N, 9.07; O, 2.59; S, 5.19

1253641-65-4

49779607

Off-white to light yellow solid powder

1.4±0.1 g/cm3

1.635

8.91

1

7

7

41

962

0

O=C(C1=NN(C2=CC=C(Cl)C=C2Cl)C(C3=CC=C(C#CC4=CC=C(C(F)(F)F)C=C4)S3)=C1CC)NN5CCCCC5

VQOCBFYUDSBDCZ-UHFFFAOYSA-N

InChI=1S/C30H25Cl2F3N4OS/c1-2-23-27(29(40)37-38-16-4-3-5-17-38)36-39(25-14-11-21(31)18-24(25)32)28(23)26-15-13-22(41-26)12-8-19-6-9-20(10-7-19)30(33,34)35/h6-7,9-11,13-15,18H,2-5,16-17H2,1H3,(H,37,40)

1-(2,4-dichlorophenyl)-4-ethyl-N-piperidin-1-yl-5-[5-[2-[4-(trifluoromethyl)phenyl]ethynyl]thiophen-2-yl]pyrazole-3-carboxamide

TM38837; TM 38837; TM38,837; 1253641-65-4; TM-38,837; 1-(2,4-dichlorophenyl)-4-ethyl-N-piperidin-1-yl-5-[5-[2-[4-(trifluoromethyl)phenyl]ethynyl]thiophen-2-yl]pyrazole-3-carboxamide; TM388371253641-65-4; CHEMBL3341897; VQOCBFYUDSBDCZ-UHFFFAOYSA-N; YD7836VJ3G; TM-38837

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 : ~41.67 mg/mL (~67.48 mM)

Solubility in Formulation 1: ≥ 4.17 mg/mL (6.75 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 41.7 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.)