Discovery of Novel N-Substituted Oxindoles as Selective M1 and M4 Muscarinic Acetylcholine Receptors Partial Agonists

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• 作者：Takaaki Sumiyoshi ; Takeshi Enomoto ; Kentaro Takai ; Yoko Takahashi ; Yasuko Konishi ; Yoshiharu Uruno ; Kengo Tojo ; Atsushi Suwa ; Harumi Matsuda ; Tomokazu Nakako ; Mutsuko Sakai ; Atsushi Kitamura ; Yasuaki Uematsu ; Akihiko Kiyoshi
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：4
• 期：2
• 页码：244-248
• 全文大小：318K
• 年卷期：v.4,no.2(February 14, 2013)
• ISSN：1948-5875

文摘

Activation of the M₁ and M₄ 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 M₁ and M₄ over M₂, M₃, and M₅. Among these oxindoles, compound 1 showed high selectivity for the M₁ and M₄ 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.

Keywords:

muscarinic acetylcholine receptor; selective agonist; partial agonist; schizophrenia; oxindole