Novel Allosteric Agonists of M1 Muscarinic Acetylcholine Receptors Induce Brain Region-Specific Responses That Correspond with Behavioral Effects in Animal Models

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 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 Ca++ 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.

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

“…Although previous studies indicate that activation of M 1 mAChRs is critical for learning, memory, and executive functions, the role of M 4 mAChRs in modulating cognitive function remains unclear Shirey et al, 2009;Digby et al, 2012;Ma et al, 2009). We found that VU0152100 alone had no effect on PPI or the acquisition of contextual fear conditioning, suggesting that M 4 may not be required for normal hippocampal learning and memory processes in young adult rats.…”

“…However, as the higher doses of amphetamine used in the cognitive studies can induce increases in both dopamine and norepinephrine (McKittrick and Abercrombie 2007), it will be important in future studies to confirm that these effects of VU0152100 are mediated predominately through reversal of dopaminergic signaling. Finally, VU0152100 provides an important M 4 -selective tool compound that used along with recently reported M 1 -selective PAMs (Ma et al, 2009;Shirey et al, 2009) or allosteric agonists (Lebois et al, 2010;Digby et al, 2012) will allow a more complete understanding of the relative roles of these two mAChR subtypes in regulating multiple aspects of cognitive function.…”

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

“…136 Studies in native tissues of M 1 mAChR-mediated responses demonstrate that while both compounds potentiate NMDA receptor currents in hippocampal pyramidal cells and induce hippocampal LTP, they are devoid of electrophysiological activity in PFC pyramidal cells. These observations correlate well with the aforementioned study in which VU0357017 demonstrated efficacy in CFC, a hippocampal-dependent animal model of cognition.…”

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

“…These data are consistent with the hypothesis that changes in mAChR signaling could contribute to the symptoms observed in schizophrenia patients. Of the five mAChR subtypes (M 1 -M 5 ), M 1 is the predominant mAChR subtype expressed in the PFC (Levey et al, 1991) and likely participates in induction of mLTD (Caruana et al, 2011) and other physiological responses that are important for PFC-dependent cognitive functions (Digby et al, 2012;Shirey et al, 2009). We now report discovery and optimization of VU0453595 as a novel, highly selective positive allosteric modulator (PAM) for M 1 that provides excellent pharmacokinetic properties and brain exposure in mice after systemic administration.…”