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Novel Positive Allosteric Modulators Bias Acetylcholine Signaling at Human M 4 Muscarinic Receptors
Author(s) -
Klein Michael Thomas,
Digby Gregory,
Niswender Colleen,
Tarr Christopher,
Poslusney Michael,
Melancon Bruce,
Wood Michael,
Lindsley Craig,
Conn P. Jeffrey
Publication year - 2013
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.27.1_supplement.1171.4
Subject(s) - allosteric regulation , functional selectivity , muscarinic acetylcholine receptor , agonist , allosteric modulator , g protein coupled receptor , antipsychotic , neuroscience , pharmacology , receptor , arrestin , signal transduction , acetylcholine , chemistry , psychosis , schizophrenia (object oriented programming) , psychology , biology , biochemistry , psychiatry
M 4 muscarinic acetylcholine receptors (mAChRs) are heavily expressed in the CNS, and activation of these receptors is thought to mediate the antipsychotic effects of the M 1 /M 4 ‐preferring agonist xanomeline. Clinical trials have shown xanomeline to be highly effective in treating the positive symptoms, negative symptoms, and cognitive deficits of schizophrenia as well as Alzheimer's type dementia. As a consequence, much interest has been placed on developing M 4 ‐selective drugs for the treatment of various forms of psychosis. To achieve robust selectivity, our group has identified M 4 ‐selective positive allosteric modulators (PAMs); these compounds have shown robust efficacy in animal models used to predict antipsychotic efficacy. In this study, we examined the ability of M 4 ‐selective PAMs to differentially modulate several intracellular signaling pathways (ERK phosphorylation, GIRK channel activation, arrestin recruitment) and differentially desensitize G‐protein‐mediated responses. Interestingly, multiple PAMs have the ability to bias the signaling of acetylcholine towards specific responses and have profound and differential effects on M 4 receptor β‐arrestin recruitment. These data indicate that M 4 allosteric ligands engender receptor conformational changes and signaling outcomes not previously described for GPCR orthosteric ligand interactions. Identification of signal bias and differential desensitization of M 4 receptors may be important for therapeutic actions of these compounds and will guide future M 4 receptor drug development efforts. Future efforts will concentrate on signaling properties that correlate with robust antipsychotic efficacy in vivo.