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

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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).

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.”

https://www.ncbi.nlm.nih.gov/pubmed/29051736

https://www.frontiersin.org/articles/10.3389/fphar.2017.00707/full

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LH-21 and Abn-CBD improve β-cell function in isolated human and mouse islets through GPR55-dependent and -independent signalling.

Diabetes, Obesity and Metabolism

“CB1 and GPR55 are GPCRs expressed by islet β-cells. Pharmacological compounds have been used to investigate their function, but off-target effects of ligands have been reported.

This study examined the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and islets from GPR55-/- mice were used to determine signalling via GPR55.

RESULTS:

Abn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca2+ ]i in human islets and islets from both GPR55+/+ and GPR55-/- mice. LH-21 also increased insulin secretion and [Ca2+ ]i in human islets and GPR55+/+ mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55-/- mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed following GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55-/- mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets.

CONCLUSIONS:

This study demonstrated that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55-/- mice suggests that designation of Abn-CBD and LH-21 as GPR55 agonist and CB1 antagonist, should be revised.”

https://www.ncbi.nlm.nih.gov/pubmed/29205751

http://onlinelibrary.wiley.com/doi/10.1111/dom.13180/abstract

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Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling.

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“Binge alcohol (ethanol) drinking is associated with profound adverse effects on our health and society. Rimonabant (SR141716A), a CB1 receptor inverse agonist, was previously shown to be effective for nicotine cessation and obesity. However, studies using rimonabant were discontinued as it was associated with an increased risk of depression and anxiety.

In the present study, we examined the pharmacokinetics and effects of AM4113, a novel CB1 receptor neutral antagonist on binge-like ethanol drinking in C57BL/6J mice using a two-bottle choice drinking-in-dark (DID) paradigm.

The results indicated a slower elimination of AM4113 in the brain than in plasma. AM4113 suppressed ethanol consumption and preference without having significant effects on body weight, ambulatory activity, preference for tastants (saccharin and quinine) and ethanol metabolism. AM4113 pretreatment reduced ethanol-induced increase in dopamine release in nucleus accumbens.

Collectively, these data suggest an important role of CB1 receptor-mediated regulation of binge-like ethanol consumption and mesolimbic dopaminergic signaling, and further points to the potential utility of CB1 neutral antagonists for the treatment of binge ethanol drinking.”

https://www.ncbi.nlm.nih.gov/pubmed/29109060

 

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Increased expression of type 1 cannabinoid (CB1) receptor among patients with rotator cuff lesions and shoulder stiffness.

:Journal of Shoulder and Elbow Surgery Home

“Shoulder stiffness is a disease manifested by pain, limited range of motion, and functional disability. The inflammatory and fibrosis processes play a substantial role in the pathogenesis of shoulder stiffness. The CB1 receptor has been recognized to mediate the processes of pathologic fibrosis.

This study investigated the role of the CB1 pathway in pathogenesis of rotator cuff lesions with shoulder stiffness.

The CB1 pathway is involved in the pathogenesis of shoulder stiffness. It may be a promising target for the treatment of rotator cuff lesions with shoulder stiffness.”

https://www.ncbi.nlm.nih.gov/pubmed/29108858

http://www.jshoulderelbow.org/article/S1058-2746(17)30589-X/fulltext

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Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts.

“Inflammatory bowel diseases (IBDs) include Crohn’s disease, and ulcerative colitis. Cannabis sativa preparations have beneficial effects for IBD patients. However, C. sativa extracts contain hundreds of compounds. Although there is much knowledge of the activity of different cannabinoids and their receptor agonists or antagonists, the cytotoxic and anti-inflammatory activity of whole C. sativa extracts has never been characterized in detail with in vitro and ex vivo colon models.

Material and Methods: The anti-inflammatory activity of C. sativa extracts was studied on three lines of epithelial cells and on colon tissue. C. sativa flowers were extracted with ethanol, enzyme-linked immunosorbent assay was used to determine the level of interleukin-8 in colon cells and tissue biopsies, chemical analysis was performed using high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance and gene expression was determined by quantitative real-time PCR.

Results: The anti-inflammatory activity of Cannabis extracts derives from D9-tetrahydrocannabinolic acid (THCA) present in fraction 7 (F7) of the extract. However, all fractions of C. sativa at a certain combination of concentrations have a significant increased cytotoxic activity. GPR55 receptor antagonist significantly reduces the anti-inflammatory activity of F7, whereas cannabinoid type 2 receptor antagonist significantly increases HCT116 cell proliferation. Also, cannabidiol (CBD) shows dose dependent cytotoxic activity, whereas anti-inflammatory activity was found only for the low concentration of CBD, and in a bell-shaped rather than dose-dependent manner. Activity of the extract and active fraction was verified on colon tissues taken from IBD patients, and was shown to suppress cyclooxygenase-2 (COX2) and metalloproteinase-9 (MMP9) gene expression in both cell culture and colon tissue.

Conclusions: It is suggested that the anti-inflammatory activity of Cannabis extracts on colon epithelial cells derives from a fraction of the extract that contains THCA, and is mediated, at least partially, via GPR55 receptor. The cytotoxic activity of the C. sativa extract was increased by combining all fractions at a certain combination of concentrations and was partially affected by CB2 receptor antagonist that increased cell proliferation. It is suggested that in a nonpsychoactive treatment for IBD, THCA should be used rather than CBD.”

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Pharmacological augmentation of endocannabinoid signaling reduces the neuroendocrine response to stress.

Psychoneuroendocrinology

“Activation of the hypothalamic-pituitary-adrenal axis (HPA) is critical for survival when the organism is exposed to a stressful stimulus. The endocannabinoid system (ECS) is currently considered an important neuromodulator involved in numerous pathophysiological processes and whose primary function is to maintain homeostasis. In the tissues constituting the HPA axis, all the components of the ECS are present and the activation of this system acts in parallel with changes in the activity of numerous neurotransmitters, including nitric oxide (NO). NO is widely distributed in the brain and adrenal glands and recent studies have shown that free radicals, and in particular NO, may play a crucial role in the regulation of stress response. Our objective was to determine the participation of the endocannabinoid and NOergic systems as probable mediators of the neuroendocrine HPA axis response to a psychophysical acute stress model in the adult male rat. Animals were pre-treated with cannabinoid receptors agonists and antagonists at central and systemic level prior to acute restraint exposure. We also performed in vitro studies incubating adrenal glands in the presence of ACTH and pharmacological compounds that modifies ECS components. Our results showed that the increase in corticosterone observed after acute restraint stress is blocked by anandamide administered at both central and peripheral level. At hypothalamic level both cannabinoid receptors (CB1 and CB2) are involved, while in the adrenal gland, anandamide has a very potent effect in suppressing ACTH-induced corticosterone release that is mainly mediated by vanilloid TRPV1 receptors. We also observed that stress significantly increased hypothalamic mRNA levels of CB1 as well as adrenal mRNA levels of TRPV1 receptor. In addition, anandamide reduced the activity of the nitric oxide synthase enzyme during stress, indicating that the anti-stress action of endocannabinoids may involve a reduction in NO production at hypothalamic and adrenal levels. In conclusion, an endogenous cannabinoid tone maintains the HPA axis in a stable basal state, which is lost with a noxious stimulus. In this case, the ECS dampens the response to stress allowing the recovery of homeostasis. Moreover, our work further contributes to in vitro evidence for a participation of the endocannabinoid system by inhibiting corticosterone release directly at the adrenal gland level.”

https://www.ncbi.nlm.nih.gov/pubmed/29065362

http://www.psyneuen-journal.com/article/S0306-4530(17)30614-5/fulltext

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

 Image result for frontiers pharmacology

“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 vivopharmacodynamic 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.”

https://www.ncbi.nlm.nih.gov/pubmed/29051736

https://www.frontiersin.org/articles/10.3389/fphar.2017.00707/full

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Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.

Molecular Metabolism

“In visceral obesity, an overactive endocannabinoid/CB1 receptor (CB1R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB1R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB1R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined.

METHODS:

We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.

RESULTS:

Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY+ than with POMC+ ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY-/- mice kept on a high-fat diet.

CONCLUSIONS:

Peripheral CB1R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC.”

https://www.ncbi.nlm.nih.gov/pubmed/29031713

http://www.molmetab.com/article/S2212-8778(17)30327-7/fulltext

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Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy.

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“Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.”

https://www.ncbi.nlm.nih.gov/pubmed/29030466

http://jasn.asnjournals.org/content/early/2017/10/12/ASN.2017040371

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Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica.

Cytokine

“We explored the role of interleukin 1 (IL-1) in two models of pulmonary fibrosis (PF), elicited in mice by the intra-tracheal instillation of bleomycin or silica

This study indicates that IL-1ra might be useful for the treatment of incipient or established pulmonary fibrosis.”

https://www.ncbi.nlm.nih.gov/pubmed/7683505

http://www.sciencedirect.com/science/article/pii/104346669390024Y?via%3Dihub

“Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. Cannabinoids (CBs) also exert potent anti-inflammatory and neuroprotective effects.  We report for the first time that both CB1 and CB2 receptors modulate release of endogenous IL-1ra. Endogenous IL-1ra is essential for the neuro-protective effects of CBs against excessive activation of glutamate receptors (excitotoxicity). These data suggest a novel neuroprotective mechanism of action for CBs in response to inflammatory or excitotoxic insults that is mediated by both CB1 and CB2 receptor-dependent pathways.”  https://www.ncbi.nlm.nih.gov/pubmed/12878687

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