title: Discovery of novel N-substituted oxindoles as selective m1 and m4 muscarinic acetylcholine receptors partial agonists.
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.
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takai
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Konishi
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Uruno
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tojo
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suwa
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nakako
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Drug Discovery Division, Dainippon Sumitomo Pharma Co. Ltd. , 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kiyoshi
keywords: muscarinic acetylcholine receptor; oxindole; partial agonist; schizophrenia; selective agonist