Document Detail

Profiling two indole-2-carboxamides for allosteric modulation of the CB1 receptor.
MedLine Citation:
PMID:  23205875     Owner:  NLM     Status:  MEDLINE    
Allosteric modulation of G-protein coupled receptors (GPCRs) represents a novel approach for fine-tuning GPCR functions. The cannabinoid CB1 receptor, a GPCR associated with the CNS, has been implicated in the treatment of drug addiction, pain, and appetite disorders. We report here the synthesis and pharmacological characterization of two indole-2-carboxamides:5-chloro-3-ethyl-1-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ICAM-a) and 5-chloro-3-pentyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ICAM-b). Although both ICAM-a and ICAM-b enhanced CP55, 940 binding, ICAM-b exhibited the strongest positive cooperativity thus far demonstrated for enhancing agonist binding to the CB1 receptor. Although it displayed negative modulatory effects on G-protein coupling to CB1, ICAM-b induced β-arrestin-mediated downstream activation of extracellular signal-regulated kinase (ERK) signaling. These results indicate that this compound represents a novel class of CB1 ligands that produce biased signaling via CB1.
Kwang H Ahn; Mariam M Mahmoud; Sushma Samala; Dai Lu; Debra A Kendall
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-07
Journal Detail:
Title:  Journal of neurochemistry     Volume:  124     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-18     Completed Date:  2013-04-19     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  584-9     Citation Subset:  IM    
Copyright Information:
© 2012 International Society for Neurochemistry.
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MeSH Terms
Allosteric Regulation / drug effects
HEK293 Cells
Indoles / chemistry,  metabolism,  pharmacology*
Piperidines / chemistry,  metabolism,  pharmacology*
Protein Binding
Receptor, Cannabinoid, CB1 / chemistry*,  metabolism*
Signal Transduction / drug effects*
Grant Support
Reg. No./Substance:
0/5-chloro-3-ethyl-1-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide; 0/5-chloro-3-pentyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide; 0/Indoles; 0/Ligands; 0/Piperidines; 0/Receptor, Cannabinoid, CB1

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