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mGluR5 Negative Allosteric Modulator GRN-529 Decreases Autistic Behaviours In Mice

sekio

sekio

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National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD). An experimental compound, called GRN-529, increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors, the researchers say.
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NIMH ref

Can't find a structure for GRN-529. It seems that drugs binding to this receptor might have real potential.
 
This makes way way too much sense to me... I've always seen some of the Asperger's kids I've worked with as having ultra addictive personalities, just in respect to a few random things though.
mGluR5 activity is heavily implicated in addiction/drug learning in animal models
http://en.wikipedia.org/wiki/Metabotropic_glutamate_receptor_5

I'd be interested in seeing any papers on how mGluR5 interacts with vasopressin and oxytocin, as they seem to be other major candidates for pharmacological therapy of autism.
 
Seeing as I don't know how to post images here, ill just give you the IUPAC name for GRN-529:

(4-(difluoromethoxy)-3-(pyridin-2-ylethynyl)phenyl)(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)methanone

Chemdraw builds it fine.
 
Here it is:

34644d4.jpg
 
The molecule seems to contain the same basic structure (pyridyl and phenyl connected by acetylene) as MPEP...

Interestingly, there's some evidence that MGluR5 antagonists are self-administered by animals, so there could also be some potential for recreational use...

I have Aspergers, and I don't really think there will ever be a drug that will 'cure' me. Anti-addictive properties of MGluR modulators could help me with my drink problem, though. Also, theres a theory that autism spectrum disorders are caused by an excess of endogenous opioid peptides in the brain, and naltrexone has been tested as a pharmacotherapy for autism. (naltrexone is also used in the Sinclair method treatment of alcoholism)
 
Epsilon Alpha said:
I'd be interested in seeing any papers on how mGluR5 interacts with vasopressin and oxytocin, as they seem to be other major candidates for pharmacological therapy of autism.
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A quick Google search gave this result:

http://ajpregu.physiology.org/content/281/2/R452.full
Abstract
The effect of metabotropic glutamate receptor (mGluR) activation on vasopressin (VP) and oxytocin (OT) release was evaluated using explants of the hypothalamoneurohypophysial system. (+/−)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), an agonist at groups I and II mGluRs, increased VP and OT release in a concentration-dependent manner. A role for group I mGluRs in VP and OT release was demonstrated by the ability of a group I-specific mGluR antagonist, 1-aminoindan-1,5-idicarboxylic acid (AIDA), to block the effect of t-ACPD and the ability of a group I-specific agonist, (R,S)-3,5-dihydroxyphenylglycine, to significantly increase both VP (P = 0.0029) and OT (P = 0.0032) release. However, AIDA did not alter VP or OT release induced by a ramp increase in osmolality of the perifusion medium. The role of group III mGluRs was examined using L(+)-2-amino-4-phosphonobutyric acid (L-AP4), an agonist of these receptors. L-AP4 did not change basal release of VP or OT and did not prevent osmotically stimulated hormone release. Thus mGluR activation stimulates VP and OT release, but it is not required for osmotic stimulation of hormone release.
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The mGluR5 is def an interesting pharmacological target especially in terms of its putative role in addiction behaviors.


Abstract: In animal models of addiction, reducing glutamate stimulation of the metabotropic glutamate receptor 5 (mGluR5) inhibits drug-seeking. The present study used the reinstatement model of cocaine-seeking to show that blockade of mGluR5 directly in the core subcompartment of the nucleus accumbens (NAcore) prevented both conditioned cue- and cocaine-reinstated drug-seeking. Consistent with this finding, microinjection of the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine into the NAcore produced modest reinstatement of lever pressing when given alone and significantly potentiated cue-induced reinstatement. Homer proteins are contained in the post-synaptic density and regulate mGluR5 intracellular signaling and trafficking to the membrane. Microinjecting a membrane permeable peptide antagonist of Homer binding to mGluR5 into the NAcore also inhibited cue- and cocaine-reinstated lever pressing. However, this peptide did not change the surface expression of mGluR5, indicating that the peptide inhibitor did not alter the surface trafficking of mGluR5. Taken together, these data show that mGluR5 inhibition and stimulation in the NAcore can regulate cocaine-seeking, and demonstrate that one mechanism for this effect is via interactions with Homer proteins.
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http://www.ncbi.nlm.nih.gov/pubmed/22340009
 
It's my understanding that mglur5 and 5HT2a receptors operate with a sort of push pull mechanism in some areas of the brain, meaning inhibition of one will facilitate activation of the other. I wonder if that has any relevance to this effect?
 
has anyone else noticed that GRN-529 looks a lot like a cannabinoid antagonist?
 
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