Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptorss

The muscarinic acetylcholine receptor subtype 1 (M-1) 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 M-1 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 M-2 and M-3. Therefore, drug discovery efforts targeting the M-1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M-1 receptor ligands have been described, which exhibit excellent selectivity for M-1 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-cyano4-( 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 M-1 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 M-1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M-1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M-1 receptor selective activators.