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Novel Allosteric Agonists of M1 Muscarinic Acetylcholine Receptors Induce Brain Region-Specific Responses That Correspond with Behavioral Effects in Animal Models.
- Source :
- Journal of Neuroscience; 6/20/2012, Vol. 32 Issue 25, p8532-8544, 13p
- Publication Year :
- 2012
-
Abstract
- M<subscript>1</subscript> muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M<subscript>1</subscript> receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Herewedescribe the characterization of two novel M<subscript>1</subscript> allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M<subscript>1</subscript> coupling to different signaling pathways including Ca<superscript>2+</superscript> and &bgr;-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M<subscript>1</subscript> to specific signaling pathways leads to selective actionsonsomebut not allM1-mediated responses in brain circuits. These novel M<subscript>1</subscript> allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M<subscript>1</subscript>-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M<subscript>1</subscript> agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M<subscript>1</subscript> allosteric agonists can differentially regulate coupling of M<subscript>1</subscript> to different signaling pathways, and this candramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02706474
- Volume :
- 32
- Issue :
- 25
- Database :
- Complementary Index
- Journal :
- Journal of Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 77691368
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.0337-12.2012