• Catherine A Thorn, Joshua Moon, Clinton A Bourbonais, John Harms, Jeremy R Edgerton, Eda Stark, Stefanus J Steyn, Christopher R Butter, John T Lazzaro, Rebecca E O'Connor, and Michael Popiolek.
• Primary Pharmacology Group , Pfizer Worldwide Research and Development , Groton , Connecticut 06340 , United States.
• Acs Chem Neurosci. 2019 Mar 20; 10 (3): 1753-1764.

AbstractPreclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer's diseases. This is best exemplified by clinical observations with xanomeline, the efficacy of which is thought to be mediated through co-activation of the M1 and M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to the actions of selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3'-5'-cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation in the striatum, hippocampus, and prefrontal cortex. We additionally assessed the effects of xanomeline on hippocampal electrophysiological signatures in rats using ex vivo recordings from CA1 (Cornu Ammonis 1) as well as in vivo hippocampal theta. As expected, xanomeline's effects across these readouts were consistent with activation of both M1 and M4 mAChRs; however, differences were observed across different brain regions, suggesting non-uniform activation of these receptor subtypes in the central nervous system. Interestingly, despite having nearly equal in vitro potency at the M1 and the M4 mAChRs, during in vivo assays xanomeline produced M4-like effects at significantly lower brain exposures than those at which M1-like effects were observed. Our results raise the possibility that clinical efficacy observed with xanomeline was driven, in part, through its non-uniform activation of mAChR subtypes in the central nervous system and, at lower doses, through preferential agonism of the M4 mAChR.

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