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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
23
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pubmed:dateCreated |
2003-11-12
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pubmed:abstractText |
The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive. The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, N-desmethylclozapine. Recent clinical and preclinical evidences of the antipsychotic activity of the muscarinic agonist xanomeline prompted us to investigate the effects of N-desmethylclozapine on cloned human M1-M5 muscarinic receptors. N-desmethylclozapine preferentially bound to M1 muscarinic receptors with an IC50 of 55 nM and was a more potent partial agonist (EC50, 115 nM and 50% of acetylcholine response) at this receptor than clozapine. Furthermore, pharmacological and site-directed mutagenesis studies suggested that N-desmethylclozapine preferentially activated M1 receptors by interacting with a site that does not fully overlap with the acetylcholine orthosteric site. As hypofunction of N-methyl-d-aspartate (NMDA) receptor-driven neuronal ensembles has been implicated in psychotic disorders, the neuronal activity of N-desmethylclozapine was electrophysiologically investigated in hippocampal rat brain slices. N-desmethylclozapine was shown to dose-dependently potentiate NMDA receptor currents in CA1 pyramidal cells by 53% at 100 nM, an effect largely mediated by activation of muscarinic receptors. Altogether, our observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation. These observations raise the possibility that N-desmethylclozapine contributes to clozapine's clinical activity in schizophrenics through modulation of both muscarinic and glutamatergic neurotransmission.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/14595031-10063486,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14595031-10208296,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14595031-10531410,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/14595031-9818633
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
100
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
13674-9
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:14595031-Allosteric Site,
pubmed-meshheading:14595031-Animals,
pubmed-meshheading:14595031-Brain,
pubmed-meshheading:14595031-Cell Line,
pubmed-meshheading:14595031-Clozapine,
pubmed-meshheading:14595031-Cricetinae,
pubmed-meshheading:14595031-DNA, Complementary,
pubmed-meshheading:14595031-Dose-Response Relationship, Drug,
pubmed-meshheading:14595031-Electrophysiology,
pubmed-meshheading:14595031-Guanosine 5'-O-(3-Thiotriphosphate),
pubmed-meshheading:14595031-Hippocampus,
pubmed-meshheading:14595031-Humans,
pubmed-meshheading:14595031-Inhibitory Concentration 50,
pubmed-meshheading:14595031-Mutagenesis, Site-Directed,
pubmed-meshheading:14595031-Neurons,
pubmed-meshheading:14595031-Protein Binding,
pubmed-meshheading:14595031-Rats,
pubmed-meshheading:14595031-Receptor, Muscarinic M1,
pubmed-meshheading:14595031-Receptors, N-Methyl-D-Aspartate,
pubmed-meshheading:14595031-Time Factors
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pubmed:year |
2003
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pubmed:articleTitle |
N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity.
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pubmed:affiliation |
Department of Neuroscience, Merck & Co. Inc., West Point, PA 19486, USA. cyrille_sur@merck.com
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pubmed:publicationType |
Journal Article
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