Document Detail

Functional selectivity in cannabinoid signaling.
MedLine Citation:
PMID:  20021440     Owner:  NLM     Status:  MEDLINE    
Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.
E V Varga; T Georgieva; S Tumati; I Alves; Z Salamon; G Tollin; H I Yamamura; W R Roeske
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review    
Journal Detail:
Title:  Current molecular pharmacology     Volume:  1     ISSN:  1874-4702     ISO Abbreviation:  Curr Mol Pharmacol     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2009-12-21     Completed Date:  2010-02-24     Revised Date:  2011-12-29    
Medline Journal Info:
Nlm Unique ID:  101467997     Medline TA:  Curr Mol Pharmacol     Country:  United Arab Emirates    
Other Details:
Languages:  eng     Pagination:  273-84     Citation Subset:  IM    
University of Arizona, College of Medicine, Department of Pharmacology, Tucson, AZ 85724, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Central Nervous System / drug effects
Cyclic AMP / metabolism
Immunomodulation / drug effects
Ion Channels / metabolism
Mitogen-Activated Protein Kinases / metabolism
Receptors, Cannabinoid / agonists*,  metabolism
Receptors, G-Protein-Coupled / metabolism
Signal Transduction
Grant Support
Reg. No./Substance:
0/Ion Channels; 0/Receptors, Cannabinoid; 0/Receptors, G-Protein-Coupled; 60-92-4/Cyclic AMP; EC Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Can increased food intake improve psychosis? A brief review and hypothesis.
Next Document:  Induced pluripotent stem cells, new tools for drug discovery and new hope for stem cell therapies.