Discovery of Novel N-Substituted Oxindoles as Selective M1 and M4 Muscarinic Acetylcholine Receptors Partial Agonists
| Autor: | Yoko Takahashi, Yasuaki Uematsu, Mutsuko Sakai, Atsushi Kitamura, Harumi Matsuda, Kentaro Takai, Akihiko Kiyoshi, Takaaki Sumiyoshi, Yasuko Konishi, Tomokazu Nakako, Kengo Tojo, Atsushi Suwa, Yoshiharu Uruno, Takeshi Enomoto |
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| Rok vydání: | 2013 |
| Předmět: |
Acetylcholine binding
Nicotinic agonist Chemistry Organic Chemistry Drug Discovery Muscarinic acetylcholine receptor Muscarinic acetylcholine receptor M5 Muscarinic acetylcholine receptor M4 Muscarinic acetylcholine receptor M3 Muscarinic acetylcholine receptor M2 Muscarinic acetylcholine receptor M1 Pharmacology Biochemistry |
| Zdroj: | ACS Medicinal Chemistry Letters. 4:244-248 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/ml300372f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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