A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

Wu, Yen‐Ku; Yeh, Ching Fang; Ly, Tai Wei; Hung, Ming‐Shiu

doi:10.2174/156802611795860997

Cited by 22 publications

(16 citation statements)

References 35 publications

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“…The adverse psychoactive effects of CB 1 blockage in the brain could be greatly attenuated if a CB 1 selective antagonist was to target peripheral tissues and not cross the blood-brain barrier (BBB). Initial investigations into the development of peripherally targeted CB 1 compounds has met with disappointing results, showing that the positive effects were short lived or did not share the same effects as the brain penetrating parent compound, Rimonabant [105]. Further research, however, has seen the development of a range of newer, more effective peripheral CB 1 targeted compounds ( figure 3).…”

Section: Peripheral Targeted Cb 1 Antagonism-the Road Forwardmentioning

confidence: 99%

The cannabinoid receptor 1 and its role in influencing peripheral metabolism

O’Keefe

Simcocks

Hryciw

et al. 2013

Diabetes Obesity Metabolism

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Evidence from in vitro and in vivo studies has demonstrated the deleterious pathological effects of a dysregulated endocannabinoid system. Increased stimulation of the cannabinoid receptor 1 (CB1 ) and subsequent downstream cellular signalling are both causative in the deleterious pathological effects observed in a number of diseases. When the CB1 cell signalling cascade is blocked, this results in whole body weight-loss, leading to a reduction in obesity and associated co-morbidities. In the central nervous system; however, CB1 antagonism results in adverse psychological side effects. Blockade of CB1 via peripheral acting compounds that do not cross the blood-brain barrier have been determined to have beneficial effects in metabolic tissues such as the liver and skeletal muscle. These results support the notion that peripheral blockade of CB1 using pharmacological antagonists is a viable target for the treatment of the current epidemic of obesity and its associated co-morbidities.

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Section: Peripheral Targeted Cb 1 Antagonism-the Road Forwardmentioning

confidence: 99%

The cannabinoid receptor 1 and its role in influencing peripheral metabolism

O’Keefe

Simcocks

Hryciw

et al. 2013

Diabetes Obesity Metabolism

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“…The distribution of TXX-522 in brain tissue and plasma was first studied following intravenous administration to normal rats after distribution had reached a steady state as described previously (Wu et al, 2011). This analysis identified only 2% of TXX-522 in the brain tissue, and most of this compound was retained in peripheral tissues while under the same condition, >60% of SR141716A was distributed in the brain tissue.…”

Section: Discussionmentioning

confidence: 99%

Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

Chen¹,

Shui²,

Liu

et al. 2017

Front. Pharmacol.

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The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R) antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects. In the current study, a novel compound (TXX-522) was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A). Docking assays indicate that TXX-522 was bound with the CB1R in a mode similar to that of SR141716A. TXX-522 showed good binding, CB1R-selectivity (over the CB2R), and functional antagonist activities in a range of in vitro molecular and cellular assays. In vivo analysis of the steady state distribution of TXX-522 in the rat brain and blood tissues and the assay of its functional effects on CB1R activity collectively showed that TXX-522 showed minimal brain penetration. Moreover, the in vivo pharmacodynamic study further revealed that TXX-522 had good oral bioavailability and a potent anti-obesity effect, and ameliorated insulin resistance in high-fat diet-induced obese mice. No impact on food intake was observed in this model, confirming the limited brain penetration of this compound. Thus, the current study indicates that TXX-522 is a novel and potent peripherally acting selective CB1R antagonist with the potential to control obesity and related metabolic disorders.

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“…The role of CB1 receptors for normal micturition was confirmed by administration of rimonabant, a CB1 receptor antagonist, which caused urodynamic changes in the WT mouse similar to those found in the CB1 KO mouse. As rimonabant is known to cross the blood–brain‐barrier (BBB) , it can only be speculated on whether or not the CB1 receptor‐related changes in micturition are mainly related to a CNS or peripheral nervous site of action (or both). One should keep in mind that genes can compensate for each other especially knowing that CB1 and CB2 share intracellular pathways (Gi/0 protein).…”

Section: Discussionmentioning

confidence: 99%

Bladder function in a cannabinoid receptor type 1 knockout mouse

et al. 2013

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Objective• To evaluate bladder function in an established cannabinoid type 1 (CB1) receptor knockout (KO) mouse model via organ-bath (in vitro) and urodynamic (cystometric; in vivo) experiments. Materials and Methods• In all, 20 8-week-old female wildtype (WT) mice (C57BL/6) and 20 age-matched CB1 KO mice were used. • Six mice from each group were used for the organ-bath experiments, where the contractile responses of bladder tissue strips after carbachol exposure (carbachol concentration response curve [CCRC]; myogenic contraction) and during electrical field stimulation (EFS; neurogenic contraction) were assessed.• In all, 14 mice per group were used for cystometric experiments without any anaesthesia, in which standard urodynamic variables were assessed 3 days after bladder catheterisation. Results• The CCRCs of bladder strips from CB1 KO mice were similar to those of WT mice. However, during EFS the bladder strips from the CB1 KO mice had significantly lower contractile responses than WT preparations, Conclusions• In vitro, bladder strips from CB1 KO mice responded to muscarinic receptor stimulation similarly as the WT controls, but were less responsive to electrical stimulation of nerves. In vivo, CB1 KO mice had a higher micturition frequency and more spontaneous activity than WT mice.• The present findings suggest that CB1 receptors are involved in peripheral and central nervous control of micturition.

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A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

Cited by 22 publications

References 35 publications

The cannabinoid receptor 1 and its role in influencing peripheral metabolism

The cannabinoid receptor 1 and its role in influencing peripheral metabolism

Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

Bladder function in a cannabinoid receptor type 1 knockout mouse

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