Uruno Yoshiharu, Konishi Yasuko, Suwa Atsushi, Takai Kentaro, Tojo Kengo, Nakako Tomokazu, Sakai Mutsuko, Enomoto Takeshi, Matsuda Harumi, Kitamura Atsushi, Sumiyoshi Takaaki
Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5357-61. doi: 10.1016/j.bmcl.2015.09.032. Epub 2015 Sep 12.
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).
我们设计并合成了一系列二氢喹唑啉酮衍生物作为选择性M1和M4毒蕈碱型乙酰胆碱受体激动剂。将N-乙氧羰基哌啶单元引入到一个高通量筛选命中化合物中，随后对胺连接基和氨基甲酰部分进行优化，从而确定化合物1为一个潜在候选物。所确定的化合物1对M1和M4毒蕈碱型乙酰胆碱受体表现出高选择性，并具有M4部分激动活性。此外，化合物1显示出良好的脑渗透性，并能逆转大鼠中甲基苯丙胺诱导的运动亢进（皮下注射半数有效剂量ED50 = 3.0 mg/kg）。
