Document Detail


A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling.
MedLine Citation:
PMID:  23348500     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5-mediated physiologic responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.
Authors:
M J Noetzel; K J Gregory; P N Vinson; J T Manka; S R Stauffer; C W Lindsley; C M Niswender; Z Xiang; P J Conn
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Molecular pharmacology     Volume:  83     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-20     Completed Date:  2013-05-14     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  835-47     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Allosteric Regulation / drug effects*,  physiology
Animals
Benzamides / metabolism*,  pharmacology*
Binding Sites / drug effects,  physiology
Cells, Cultured
Female
HEK293 Cells
Humans
Male
Phthalimides / metabolism*,  pharmacology*
Rats
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / agonists,  antagonists & inhibitors,  physiology*
Signal Transduction / drug effects*,  physiology
Grant Support
ID/Acronym/Agency:
1R01DA023947/DA/NIDA NIH HHS; 2R01 MH062646-13/MH/NIMH NIH HHS; 2R01NS031373-16A2/NS/NINDS NIH HHS; 5 U54 MH84659-03/MH/NIMH NIH HHS; 5 U54 MH84659-03S1/MH/NIMH NIH HHS; F32NS071746/NS/NINDS NIH HHS; R01 MH062646/MH/NIMH NIH HHS; R01 NS031373/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Benzamides; 0/N-(4-chloro-2-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)phenyl)-2-hydroxybenzamide; 0/Phthalimides; 0/Receptor, Metabotropic Glutamate 5; 0/Receptors, Metabotropic Glutamate
Comments/Corrections
Erratum In:
Mol Pharmacol. 2013 Oct;84(4):654

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


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