Dataset Information

Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies.

ABSTRACT: Medicinal chemistry has produced small-molecule agents with drug-like character that potently and safely modulate the activity of discrete endocannabinoid system components as potential treatments for medical disorders, including various psychiatric conditions. Two cannabinoid (CB) receptors (CB1 and CB2) currently represent prime endocannabinoid-system therapeutic targets for ligands that either mimic endocannabinoid signalling processes and/or potentiate endocannabinoid-system activity (agonists) or attenuate pathologically heightened endocannabinoid-system transmission (antagonists). Two endocannabinoid deactivating enzymes, fatty acid amide hydrolase (FAAH) and soluble monoacylglycerol lipase (MGL), are increasingly prominent targets for inhibitors that indirectly potentiate endocannabinoid-system signalling. Continued profiling of drug candidates in relevant disease models, identification of additional cannabinoid-related therapeutic targets, and validation of new pharmacological modes of endocannabinoid system modulation will undoubtedly invite further translational efforts in the cannabinoid field for treating psychiatric disorders and other medical conditions.

SUBMITTER: Janero DR

PROVIDER: S-EPMC5531754 | biostudies-other | 2009 Apr

REPOSITORIES: biostudies-other

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Publications

Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies.

Janero David R DR Vadivel Subramanian K SK Makriyannis Alexandros A

International review of psychiatry (Abingdon, England) 20090401 2

Medicinal chemistry has produced small-molecule agents with drug-like character that potently and safely modulate the activity of discrete endocannabinoid system components as potential treatments for medical disorders, including various psychiatric conditions. Two cannabinoid (CB) receptors (CB1 and CB2) currently represent prime endocannabinoid-system therapeutic targets for ligands that either mimic endocannabinoid signalling processes and/or potentiate endocannabinoid-system activity (agonis ...[more]

PMID: 19367506

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Project description:Endogenous signaling lipids ("endocannabinoids") functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems including type-2 diabetes, atherothrombosis, inflammation, and immune disorders. Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.

Dataset Information

Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies.

Publications

Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies.

Similar Datasets

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