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NMDA receptor *agonist*

yeah, it'd be pretty rare that both an agonist and an antagonist at the same receptor would be recreational.

kappa almost is.
 
Hammilton said:
yeah, it'd be pretty rare that both an agonist and an antagonist at the same receptor would be recreational.

kappa almost is.
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I figured it wouldn't be recreational, but was wondering if it made everything 'seem too real' or 'matter too much' :-P
 
Nagelfar said:
Ketamine, PCP, DXM etc., are NMDA receptor "antagonists", is there such a drug as NMDA receptor *agonists*, and what would they do?
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Depends on the site. If it's an agonist of the glycine site of NMDA receptors it can be quite helpful for certain conditions.


Eur Arch Psychiatry Clin Neurosci. 2008 Feb;258(1):16-27. Epub 2007 Sep 27.Click here to read Links
Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site.
Shim SS, Hammonds MD, Kee BS.

Case Western Reserve University School of Medicine, Department of Psychiatry, Cleveland VA Medical Center Psychiatric Services 116 A(W), Cleveland, Ohio 44106, USA. [email protected]

N-methyl-D-aspartate receptor (NMDAR) hypo-function theory of schizophrenia proposes that impairment in NMDAR function be associated with the pathophysiology of schizophrenia and suggests that enhancement of the receptor function may produce efficacy for schizophrenia. Consistent with this theory, for the last decade, clinical trials have demonstrated that the enhancement of NMDAR function by potentiating the glycine site of the receptor is efficacious in the treatment of schizophrenia. Full agonists of the glycine site, glycine and D-serine and a glycine transporter-1 inhibitor, sarcosine, added to antipsychotic drugs, have been shown to be effective in the treatment of negative symptoms and possibly cognitive symptoms without significantly affecting the positive symptoms of schizophrenia. A partial agonist of the glycine site, D-cycloserine, added to antipsychotic drugs, can be effective for the negative symptoms at the therapeutic doses. However, these drugs have not shown clinical efficacy when added to clozapine, suggesting that the interactions of clozapine and the glycine site potentiators may be different from those of other antipsychotic drugs and the potentiators. This article suggests that the glycine site potentiators may produce efficacy for negative and cognitive symptoms by blocking apoptosis-like neuropathological processes in patients with chronic schizophrenia and thereby can deter progressive deterioration of the disorder. This article proposes a polypharmacy of glycine site potentiators augmented with antipsychotic drugs to control positive and negative symptoms in a synergistic manner and block deterioration in schizophrenia. Since the NMDAR complex consists of multiple sites modulating receptor functions, the efficacy of glycine site potentiators for schizophrenia suggests the possibility that manipulation of other modulating sites of the NMDAR can also be efficacious in the treatment of schizophrenia.
 
Full agonists are kind of like that sensation when you put a shotgun in your mouth and pull the trigger, but a little slower.
 
How are they not causing neurotoxicity in use for schizophrenia testing then? Not that I disagree, full agonists are going to bugger NMDAergic neurones in the same way that domoic acid does a number on the hippocampus by destroying AMPAergic neurones.

And the same seizure and neurotoxicity, yup, glutamatergic full agonists are as neurotoxic as the efficacy at glutamate receptors.

Does this apply only to ionotropic receptors? as I have read here and there of some use of subtype selective agonists for mGLuRs of various kinds.
 
AFAIK the default state of the NMDAr is 'off', with the central ion channel blocked by Mg+ , only receptors with constituitive activity can have inverse agonists AFAIK, although please correct me if I screwed up, I'm tired :P so, I don't think an inverse agonist is possible at NMDA.
 
I really don't know for sure, but I would reckon that some are open and some are closed, and this changes from time to time, which are open and which are closed. For some reason I'd thought DXM and Ketamine, etc. 'closed' the receptors, thus not allowing as much sensory input through. My understanding is quite limited though to how exactly NMDA receptors work.
 
NMDA antagonists block glutamate from agonizing the receptor, which keeps the neuron from firing action potentials, thereby acting in an inhibitory fashion. Glutamate is a fast acting signalling molecule which in small, exacting amounts leads to things like perception and learning, but if unilaterally overagonized results in apoptosis of neurons.

It should be noted glutamate is the actual endogenous ligand, not NMDA. Unbound NMDA receptors will have closed cation channels.
 
Limpet_Chicken said:
AFAIK the default state of the NMDAr is 'off', with the central ion channel blocked by Mg+ , only receptors with constituitive activity can have inverse agonists AFAIK, although please correct me if I screwed up, I'm tired :P so, I don't think an inverse agonist is possible at NMDA.
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I had thought they existed as tetramers or pentamers that contracted hydrophobic regions at the center of the protein structure to block the transport of cations. Magnesium is an antagonist because it gets physically stuck in front of this region, then is expelled when the neuron depolarizes.
 
Limpet_Chicken said:
How are they not causing neurotoxicity in use for schizophrenia testing then? Not that I disagree, full agonists are going to bugger NMDAergic neurones in the same way that domoic acid does a number on the hippocampus by destroying AMPAergic neurones.
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Modulators at the glycine site are different from NMDA agonists. There are other allosteric sites on the receptor surface to which other molecules bond too eg polyamines.
 
It would cause a downstream excitatory activation in the cell, very much like glutamate itself.
 
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