精神病
抗精神病药
化学
赫尔格
反激动剂
5-HT2C受体
兴奋剂
药理学
非定型抗精神病薬
多巴胺受体D2
抗精神病薬
受体
内科学
精神分裂症(面向对象编程)
心理学
精神科
5-羟色胺受体
血清素
医学
生物化学
钾通道
作者
Takuya Oguma,Kohei Jino,Kenji Nakahara,Hidetsugu Asada,Kouki Fuchino,Kazuhiko Nagatani,Kensuke Kouki,Ryuji Okamoto,Nobuhiko Takai,Ken Koda,Shizυo Fujita,Yoshinori Sekiguchi,Kazuya Yasuo,Kei Mayumi,Akihisa Abe,Masaaki Imono,Naotaka Horiguchi,So Iwata,Ken‐ichi Kusakabe
标识
DOI:10.1021/acs.jmedchem.4c01244
摘要
Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.
科研通智能强力驱动
Strongly Powered by AbleSci AI