The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Perspectives in Medicinal Chemistry, Journal Year: 2016, Volume and Issue: 8

Published: Jan. 1, 2016

The cannabinoids are members of a deceptively simple class terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (-)-Δ 9 -tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery THC and related cannabinoids, synthetic semisynthetic classical analogs have been evaluated to help define binding modes structure–CB1/CB2 functional activity relationships. This perspective will examine with particular emphasis on structure–activity relationship five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, cyclohexenyl C-ring. Cumulative studies date helped critical structural elements required for potency selectivity toward CB1 CB2 and, more importantly, ushered development contemporary nonclassical modulators enhanced physicochemical profiles.

Language: Английский

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Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Trends in Neurosciences, Journal Year: 2019, Volume and Issue: 42(9), P. 573 - 588

Published: July 29, 2019

Language: Английский

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The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties

Neuroscience & Biobehavioral Reviews, Journal Year: 2020, Volume and Issue: 113, P. 373 - 407

Published: April 14, 2020

Language: Английский

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Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors

Translational Psychiatry, Journal Year: 2018, Volume and Issue: 8(1)

Published: April 20, 2018

Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety preclinical models. Pharmacological inhibition endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising effects rodent models with limited adverse behavioral effects, however, the efficacy dual FAAH/MAGL has not been investigated. In present study, we compared FAAH (PF-3845), MAGL (JZL184) (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed stressed conditions, (2) locomotor activity body temperature, (3) lipid levels brain (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but JZL195, was able to prevent restraint stress-induced anxiety light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment reverse foot shock-induced behavior elevated zero maze box. decreased temperature increased open-field test. Overall, did show JZL184 were more robust than examined. These results increasing either endogenous AEA 2-AG separately produces anti-anxiety stressful conditions same are obtained from simultaneously both 2-AG.

Language: Английский

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New Insights in Cannabinoid Receptor Structure and Signaling

Current Molecular Pharmacology, Journal Year: 2019, Volume and Issue: 12(3), P. 239 - 248

Published: Feb. 15, 2019

Background: Cannabinoid has long been used for medicinal purposes. signaling considered the therapeutic target treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 CB2, there are non-CB1 non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, GPR119. In addition, CB2 display allosteric binding biased signaling, revealing correlations between functional outcomes. Interestingly, new investigations indicated is functionally present within mitochondria of striated heart muscles directly regulating intramitochondrial respiration. Conclusion: this review, we summarize recent progress GPCRs, CB1/CB2 structure, Gi/Gs coupling, ligands mitochondria-localized CB1, discuss future promise research.

Language: Английский

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Endocannabinoid System Components as Potential Biomarkers in Psychiatry

Frontiers in Psychiatry, Journal Year: 2020, Volume and Issue: 11

Published: April 27, 2020

The high heterogeneity of psychiatric disorders, leads to a lack diagnostic precision. Therefore, the search biomarkers is fundamental aspect in psychiatry reach more personalized medicine. endocannabinoid system (ECS) has gained increasing interest due its involvement many different functional processes brain, including regulation emotions, motivation and cognition. This article reviews role main components ECS as certain disorders. Studies carried out rodents evaluating effects pharmacological genetic manipulation cannabinoid receptors or endocannabinoids (eCBs) degrading enzymes. Likewise, ECS-related alterations occurring at molecular level animal models reproducing some behavioral and/or neuropathological aspects disorders were reviewed. Clinical studies gene protein post-mortem brain tissue vivo blood, plasma cerebrospinal fluid (CSF) samples analyzed. Furthermore, results from neuroimaging using positron emission tomography (PET) magnetic resonance (fMRI) included. review shows close receptor 1 (CB1r) stress development mood (anxiety, depression, bipolar disorder (BD)), post-traumatic (PTSD), well etiopathogenesis schizophrenia, attention deficit hyperactivity (ADHD) eating (i.e. anorexia bulimia nervosa). On other hand, recent regarding potential therapeutic action tone by inhibition eCBs enzymes, modulation 2 (CB2r) activity on anxiolytic, antidepressive antipsychotic associated Further clinical research are needed, however, current evidence suggests that may become promising improve, least part, diagnosis treatment

Language: Английский

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Polyunsaturated fatty acids and endocannabinoids in health and disease

Nutritional Neuroscience, Journal Year: 2017, Volume and Issue: 21(10), P. 695 - 714

Published: July 7, 2017

Polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic EPA) or omega-6 (arachidonic ARA) synthesized from membrane phospholipids used as a precursor for endocannabinoids (ECs). They mediate significant effects in the fine-tune adjustment body homeostasis. Phyto- synthetic cannabinoids also rule daily life billions worldwide, they involved obesity, depression drug addiction. Consequently, there is growing interest to reveal novel active compounds this field. Cloning cannabinoid receptors 90s identification endogenous mediators arachidonylethanolamide (anandamide, AEA) 2-arachidonyglycerol (2-AG), led characterization endocannabinoid system (ECS), together with their metabolizing enzymes transporters. Today, ECS known be diverse functions such appetite control, food intake, energy balance, neuroprotection, neurodegenerative diseases, stroke, mood disorders, emesis, modulation pain, inflammatory responses, well cancer therapy. Western diet restriction micronutrients acids, could related altered production pro-inflammatory (e.g. eicosanoids) ECs, contributing progression cardiovascular diabetes, impairing conditions, Alzheimer' s disease. Here we review how diets based PUFAs might linked maintenance central peripheral metabolism, brain plasticity, memory learning, blood flow, genesis neural cells.

Language: Английский

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Monoacylglycerol lipase (MAGL) as a promising therapeutic target

Biochemical Pharmacology, Journal Year: 2018, Volume and Issue: 157, P. 18 - 32

Published: July 27, 2018

Language: Английский

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Role of the endocannabinoid system in drug addiction

Biochemical Pharmacology, Journal Year: 2018, Volume and Issue: 157, P. 108 - 121

Published: Sept. 12, 2018

Language: Английский

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A specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Feb. 7, 2020

Abstract Food addiction is linked to obesity and eating disorders characterized by a loss of behavioral control compulsive food intake. Here, using mouse model, we report that the lack cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents development addiction-like behavior, which associated with enhanced synaptic excitatory transmission medial prefrontal cortex (mPFC) nucleus accumbens (NAc). In contrast, chemogenetic inhibition neuronal activity mPFC-NAc pathway induces seeking. Transcriptomic analysis genetic manipulation identified increased dopamine D2 expression promotes phenotype. Our study unravels new neurobiological mechanism underlying resilience vulnerability addiction, could pave way towards novel efficient interventions for this disorder.

Language: Английский

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