Synthesis of Photoswitchable Δ9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling.

Journal of the American Chemical Society

“The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nerv-ous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly-rectifying potassium channels, as well as adenylyl cyclase.”

https://www.ncbi.nlm.nih.gov/pubmed/29161035

http://pubs.acs.org/doi/10.1021/jacs.7b06456

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Cannabinoid Receptor Type 1 Agonist ACEA Protects Neurons from Death and Attenuates Endoplasmic Reticulum Stress-Related Apoptotic Pathway Signaling.

Neurotoxicity Research

“Neurodegeneration is the result of progressive destruction of neurons in the central nervous system, with unknown causes and pathological mechanisms not yet fully elucidated. Several factors contribute to neurodegenerative processes, including neuroinflammation, accumulation of neurotoxic factors, and misfolded proteins in the lumen of the endoplasmic reticulum (ER).

Endocannabinoid signaling has been pointed out as an important modulatory system in several neurodegeneration-related processes, inhibiting the inflammatory response and increasing neuronal survival. Thus, we investigated the presumptive protective effect of the selective cannabinoid type 1 (CB1) receptor agonist) against inflammatory (lipopolysaccharide, LPS) and ER stress (tunicamycin) stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells). Cell viability analysis revealed that ACEA was able to protect against cell death induced by LPS and tunicamycin.

This neuroprotective effect occurs via the CB1 receptor in the inflammation process and via the transient receptor potential of vanilloid type-1 (TRPV1) channel in ER stress. Furthermore, the immunoblotting analyses indicated that the neuroprotective effect of ACEA seems to involve the modulation of eukaryotic initiation factor 2 (eIF2α), transcription factor C/EBP homologous protein (CHOP), and caspase 12, as well as the survival/death p44/42 MAPK, ERK1/2-related signaling pathways.

Together, these data suggest that the endocannabinoid system is a potential therapeutic target in neurodegenerative processes, especially in ER-related neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29134561

https://link.springer.com/article/10.1007%2Fs12640-017-9839-1

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Anti-migraine effect of ∆9-tetrahydrocannabinol in the female rat.

European Journal of Pharmacology

“Current anti-migraine treatments have limited efficacy and many side effects. Although anecdotal evidence suggests that marijuana is useful for migraine, this hypothesis has not been tested in a controlled experiment. Thus, the present study tested whether administration of ∆9-tetrahydrocannabinol (THC) produces anti-migraine effects in the female rat.

These data suggest that: 1) THC reduces migraine-like pain when administered at the right dose (0.32mg/kg) and time (immediately after AITC); 2) THC’s anti-migraine effect is mediated by CB1 receptors; and 3) Wheel running is an effective method to assess migraine treatments because only treatments producing antinociception without disruptive side effects will restore normal activity.

These findings support anecdotal evidence for the use of cannabinoids as a treatment for migraine in humans and implicate the CB1 receptor as a therapeutic target for migraine.”

https://www.ncbi.nlm.nih.gov/pubmed/29111112

http://www.sciencedirect.com/science/article/pii/S0014299917307239?via%3Dihub

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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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The Endocannabinoid System Differentially Regulates Escape Behavior in Mice.

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“Among the hardwired behaviors, fear or survival responses certainly belong to the most evolutionary conserved ones. However, higher animals possess the ability to adapt to certain environments (e.g., novel foraging grounds), and, therefore, those responses need to be plastic. Previous studies revealed a cell-type specific role of the endocannabinoid system in novelty fear, conditioned fear and active vs. passive avoidance in a shuttle box paradigm.

In this study we aim to investigate, whether knocking-out the cannabinoidreceptor type-1 (CB1) on cortical glutamatergic (Glu-CB1-/-) or GABAergic (GABA-CB1-/-) neurons differentially affects the level of behavioral inhibition, which could ultimately lead to differences in escape behavior.

Taken together, we could show that CB1 on cortical glutamatergic terminals is important for the acquisition of active avoidance, as the absence of CB1 on these neurons creates a bias toward inhibitory avoidance. This is the case in situations without punishment such as electric footshocks. On the contrary CB1 receptors on GABAergic neurons mediate the acquisition of passive avoidance, as the absence of CB1 on those neurons establishes a strong bias toward escape behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/29104536

https://www.frontiersin.org/articles/10.3389/fnbeh.2017.00201/full

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Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology.

Psychopharmacology

“Growing clinical and preclinical evidence suggests a potential role for the phytocannabinoid cannabidiol (CBD) as a pharmacotherapy for various neuropsychiatric disorders. In contrast, delta-9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, is associated with acute and neurodevelopmental propsychotic side effects through its interaction with central cannabinoidtype 1 receptors (CB1Rs). CB1R stimulation in the ventral hippocampus (VHipp) potentiates affective memory formation through inputs to the mesolimbic dopamine (DA) system, thereby altering emotional salience attribution. These changes in DA activity and salience attribution, evoked by dysfunctional VHipp regulatory actions and THC exposure, could predispose susceptible individuals to psychotic symptoms. Although THC can accelerate the onset of schizophrenia, CBD displays antipsychotic properties, can prevent the acquisition of emotionally irrelevant memories, and reverses amphetamine-induced neuronal sensitization through selective phosphorylation of the mechanistic target of rapamycin (mTOR) molecular signaling pathway. This review summarizes clinical and preclinical evidence demonstrating that distinct phytocannabinoids act within the VHipp and associated corticolimbic structures to modulate emotional memory processing through changes in mesolimbic DA activity states, salience attribution, and signal transduction pathways associated with schizophrenia-related pathology.”

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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). 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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Cannabis in fat: high hopes to treat obesity.

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“Cannabinoid receptor type-1 (CB1s) is known to have a substantial impact on the regulation of energy metabolism via central and peripheral mechanisms. In this issue of the JCI, Ruiz de Azua and colleagues provide important insights into the regulation of adipocyte physiology by CB1. Mice with adipocyte-specific deletion of the CB1-encoding gene had an overall improved metabolic profile in addition to reduced body weight and total adiposity. These changes were associated with an increase in sympathetic tone of the adipose tissue and expansion of activated macrophages, both of which occurred prior to changes in body weight, lending support to a causal relationship between loss of CB1 in adipocytes and systemic metabolic changes. This work identifies adipocyte CB1s as a potential novel peripheral target for affecting systemic metabolism with diminished CNS effects.”

https://www.ncbi.nlm.nih.gov/pubmed/29035279

https://www.jci.org/articles/view/97042

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Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.

J Clin Invest

“Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care.

Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms.

In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue.

Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions.

Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.”

https://www.ncbi.nlm.nih.gov/pubmed/29035280

https://www.jci.org/articles/view/83626

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