M 1 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 1 receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M 1 allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M 1 coupling to different signaling pathways including Ca 2+ and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M 1 to specific signaling pathways leads to selective actions on some but not all M 1-mediated responses in brain circuits. These novel M 1 allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M 1-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M 1 agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M 1 allosteric agonists can differentially regulate coupling of M 1 to different signaling pathways, and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.
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