Abstract

The muscarinic acetylcholine receptor subtype 1 (M₁) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer’s disease. Indeed, the M₁ agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer’s disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M₂ and M₃. Therefore, drug discovery efforts targeting the M₁ receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M₁ receptor ligands have been described, which exhibit excellent selectivity for M₁ over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M₁ receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1,4′-bipiperidine]-1′-carboxylate). Despite their selectivity for the M₁ receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M₁ receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M₁ receptor–targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M₁ receptor selective activators.