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A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The muscarinic acetylcholine receptor (mAChR) agonist, xanomeline, attenuates amphetamine-induced activity in WT mice. This effect is abolished in mice lacking the M(4) muscarinic acetylcholine receptor (M(4) mAChR KO) and partially attenuated in mice lacking M(1) muscarinic acetylcholine receptor (M(1) mAChR KO). Collectively, these data suggest that the efficacy exhibited by xanomeline in the mouse amphetamine-induced hyperactivity model, is mediated predominantly by M(4) muscarinic acetylcholine receptors, and that M(1) muscarinic acetylcholine receptors may play a more minor role. This supports the hypothesis that activation of M(4), and to a lesser extent M(1) muscarinic acetylcholine receptors, may represent a potential target for the treatment of psychosis seen in schizophrenia.