Document Detail


Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome.
MedLine Citation:
PMID:  18155257     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
V Kiran Vemuri; David R Janero; Alexandros Makriyannis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2007-11-21
Journal Detail:
Title:  Physiology & behavior     Volume:  93     ISSN:  0031-9384     ISO Abbreviation:  Physiol. Behav.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-18     Completed Date:  2008-07-31     Revised Date:  2013-06-18    
Medline Journal Info:
Nlm Unique ID:  0151504     Medline TA:  Physiol Behav     Country:  United States    
Other Details:
Languages:  eng     Pagination:  671-86     Citation Subset:  IM    
Affiliation:
Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115-5000, United States.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cannabinoid Receptor Modulators / antagonists & inhibitors,  chemistry,  metabolism*
Endocannabinoids*
Humans
Metabolic Diseases / drug therapy,  metabolism*
Models, Biological
Obesity / drug therapy*
Receptor, Cannabinoid, CB1 / antagonists & inhibitors,  physiology
Signal Transduction / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
R01 DA007215/DA/NIDA NIH HHS; R37 DA023142/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Cannabinoid Receptor Modulators; 0/Endocannabinoids; 0/Receptor, Cannabinoid, CB1
Comments/Corrections

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