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Characterization of novel selective positive allosteric modulators (PAMS) of the M4 muscarinic acetylcholine receptor (mAChR)
Author(s) -
Brady Ashley Elizabeth,
Bridges Tom M,
Jones Carrie K,
Shirey Jana K,
Lindsley Craig W,
Conn P Jeffrey
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.714.2
Subject(s) - agonist , muscarinic acetylcholine receptor , antipsychotic , allosteric regulation , acetylcholine , neuroscience , receptor , allosteric modulator , pharmacology , long term potentiation , chemistry , schizophrenia (object oriented programming) , medicine , psychology , psychiatry
Resent clinical studies have revealed that the M 1 /M 4 preferring mAChR agonist xanomeline induces a robust antipsychotic effect in schizophrenic patients, suggesting that mAChR agonists may be efficacious in reducing psychotic symptoms in patients suffering from a variety of neurodegenerative and psychiatric disorders. Nevertheless, a lack of highly selective compounds has made it impossible to conclusively verify whether one or both of these receptor subtypes is responsible for mediating these observed clinical effects. Previous compounds developed to selectively activate mAChR receptors have failed in clinical development due to a lack of true specificity and adverse effects associated with activation of peripheral M 2 and M 3 mAChR subtypes. Here we report characterization of a series of novel, selective M4 PAMs which do not activate the receptor directly, but dramatically potentiate activation of the receptor by its natural agonist, acetylcholine. These novel M 4 ‐selective agents can now be utilized as tools to ascertain whether selective potentiation of the M4 mAChR will mimic the in vivo effects of traditional orthosteric agonists and, more importantly, to rigorously test the hypothesis that activation of M 4 has effects in animal models predictive of antipsychotic efficacy in humans. This work supported by NIMH grants MH073676‐01A1,1 F32 MH079678‐01, 1 F31 MH80559‐01 and 5T90DA022873‐02.