Abstract

M₁ 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 M₁ 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 M₁ allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M₁ coupling to different signaling pathways including Ca²⁺ and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M₁ to specific signaling pathways leads to selective actions on some but not all M₁-mediated responses in brain circuits. These novel M₁ allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M₁-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M₁ agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M₁ allosteric agonists can differentially regulate coupling of M₁ 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.