title: Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M(1) and M(4) muscarinic acetylcholine receptors agonists.
abstract: We designed and synthesized a series of dihydroquinazolinone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M1 and M4 muscarinic acetylcholine receptors with M4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50=3.0 mg/kg, sc).
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: yoshiharu-uruno@ds-pharma.co.jp.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Uruno
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Konishi
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suwa
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tojo
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nakako
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: t-sumiyo@kansai-u.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000187:drug effects; D055808:Drug Discovery; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D043588:Receptor, Muscarinic M4 / Q000819:agonists*
chemical_list: D014150:Antipsychotic Agents; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4
keywords: Antipsychotic agent; Dihydroquinazolinone derivatives; M(1) muscarinic acetylcholine receptor; M(4) muscarinic acetylcholine receptor; Muscarinic acetylcholine receptors; Partial agonist