Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist

Muller, Tania; Demizieux, Laurent; Troy-Fioramonti, S.; Buch, Chloé; Leemput, Julia; Belloir, Christine; Barros, Jean-Paul Paı̈s de; Jourdan, Tony; Passilly-Degrace, Patricia; Fioramonti, Xavier; Bon, Anne‐Marie Le; Vergès, Bruno; Robert, Jean‐Michel; Degrace, Pascal

doi:10.3390/ijms23062923

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…According to the previous studies, WT mice in the phMRI group received rimonabant (1 mg/kg) or vehicle with intraperitoneal injection. Functional EPI images of mice were collected before drug administration, 30 min after drug administration, and 60 min after drug administration. ,, The scan parameters are as followed: TE/TR = 11.3/1000 ms, FOV = 18 × 18 mm 2 , matrix size = 90 × 90 (∼89 μm in-plane resolution), slice thickness = 0.5 mm, No. of slices = 16, number of repetitions = 480, total scan time = 8 min.…”

Section: Methodsmentioning

confidence: 99%

Resting State Brain Networks under Inverse Agonist versus Complete Knockout of the Cannabinoid Receptor 1

Li,

Ye,

Wang

et al. 2024

ACS Chem. Neurosci.

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The cannabinoid receptor 1 (CB 1 ) is famous as the target of Δ 9tetrahydrocannabinol (THC), which is the active ingredient of marijuana. Suppression of CB 1 is frequently suggested as a drug target or gene therapy for many conditions (e.g., obesity, Parkinson's disease). However, brain networks affected by CB 1 remain elusive, and unanticipated psychological effects in a clinical trial had dire consequences. To better understand the whole brain effects of CB 1 suppression we performed in vivo imaging on mice under complete knockout of the gene for CB 1 (cnr1 −/− ) and also under the CB 1 inverse agonist rimonabant. We examined white matter structural changes and brain function (network activity and directional uniformity) in cnr1 −/− mice. In cnr1 −/− mice, white matter (in both sexes) and functional directional uniformity (in male mice) were altered across the brain but network activity was largely unaltered. Conversely, under rimonabant, functional directional uniformity was not altered but network activity was altered in cortical regions, primarily in networks known to be altered by THC (e.g., neocortex, hippocampal formation). However, rimonabant did not alter many brain regions found in both our cnr1 −/− results and previous behavioral studies of cnr1 −/− mice (e.g., thalamus, infralimbic area). This suggests that chronic loss of cnr1 is substantially different from short-term suppression, subtly rewiring the brain but largely maintaining the network activity. Our results help explain why pathological mutations in CB 1 (e.g., chronic pain) do not always provide insight into the side effects of CB 1 suppression (e.g., clinical depression), and thus urge more preclinical studies for any drugs that suppress CB 1 .

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Section: Methodsmentioning

confidence: 99%

Resting State Brain Networks under Inverse Agonist versus Complete Knockout of the Cannabinoid Receptor 1

Li,

Ye,

Wang

et al. 2024

ACS Chem. Neurosci.

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Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics

Malheiro

Carmo

Carvalho

et al. 2023

Pharmacological Research

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Efficacy in diet‐induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837

Cooper,

Nørregaard,

Högberg

et al. 2024

British J Pharmacology

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Background and PurposeThe cannabinoid CB1 receptor has a well‐established role in appetite regulation. Drugs antagonizing central CB1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet‐induced obese (DIO) mice for 5 weeks at doses for which CNS‐mediated effects were minimal.Experimental ApproachCompounds were tested in dose–response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study.Key ResultsTM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake.Conclusion and ImplicationsWeight loss and metabolic benefits of TM38837 are likely not CNS‐mediated but could be linked to enhanced liver exposure, which implicates intracellular CB1 receptors in hepatocytes as a possible driver of obesity and co‐morbidities.

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Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist

Cited by 3 publications

References 61 publications

Resting State Brain Networks under Inverse Agonist versus Complete Knockout of the Cannabinoid Receptor 1

Resting State Brain Networks under Inverse Agonist versus Complete Knockout of the Cannabinoid Receptor 1

Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics

Efficacy in diet‐induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837

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