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[摘要]：Activation of the M-1 and M-4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M-1 and M-4 over M-2, M-3, and M-5. Among these oxindoles, compound 1 showed high selectivity for the M-1 and M-4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects. |
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