2. Academic Validation
  3. Discovery of novel N-substituted oxindoles as selective m1 and m4 muscarinic acetylcholine receptors partial agonists

Discovery of novel N-substituted oxindoles as selective m1 and m4 muscarinic acetylcholine receptors partial agonists

  • ACS Med Chem Lett. 2013 Jan 27;4(2):244-8. doi: 10.1021/ml300372f.
Takaaki Sumiyoshi 1,  Takeshi Enomoto 1,  Kentaro Takai 1,  Yoko Takahashi 1,  Yasuko Konishi 1,  Yoshiharu Uruno 1,  Kengo Tojo 1,  Atsushi Suwa 1,  Harumi Matsuda 1,  Tomokazu Nakako 1,  Mutsuko Sakai 1,  Atsushi Kitamura 1,  Yasuaki Uematsu 1,  Akihiko Kiyoshi 1
Affiliations

Affiliation

  • 1 Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
PMID: 24900656 DOI: 10.1021/ml300372f
Abstract

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; oxindole; partial agonist; schizophrenia; selective agonist.

Figures