The realization of the therapeutic potential of targeting the M1\nmuscarinic acetylcholine receptor (mAChR) for the treatment\nof cognitive decline in Alzheimerââ?¬â?¢s disease has prompted the\ndiscovery of M1 mAChR ligands showing efficacy in alleviating\ncognitive dysfunction in both rodents and humans. Among these\nis GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-\nyl]-1H-benzimidazol-2-one), described previously as a potentM1\nreceptor allosteric agonist, which showed procognitive effects in\nrodents and improved immediate memory in a clinical nicotine\nwithdrawal test but induced significant side effects. Here we\nprovide evidence using ligand binding, chemical biology and\nfunctional assays to establish that rather than the allosteric\nmechanism claimed, GSK1034702 interacts in a bitopic manner\nat the M1 mAChR such that it can concomitantly span both\nthe orthosteric and an allosteric binding site. The bitopic\nnature of GSK1034702, together with the intrinsic agonist\nactivity and a lack of muscarinic receptor subtype selectivity\nreported here, all likely contribute to the adverse effects of\nthis molecule in clinical trials. Although they impart beneficial\neffects on learning and memory, we conclude that these\nproperties are undesirable in a clinical candidate due to the\nlikelihood of adverse side effects. Rather, our data support\nthe notion that ââ?¬Å?pureââ?¬Â positive allosteric modulators showing\nselectivity for the M1 mAChR with low levels of intrinsic\nactivity would be preferable to provide clinical efficacy with\nlow adverse responses.
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