Journal of Medicinal Chemistry p. 9488 - 9520 (2019)
Update date:2022-08-15
Topics:
Fyfe, Tim J.
Kellam, Barrie
Sykes, David A.
Capuano, Ben
Scammells, Peter J.
Lane, J. Robert
Charlton, Steven J.
Mistry, Shailesh N.
Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
View MoreAirsea(Taizhou) Pharmaceutical Limited
Contact:+86-576-88057622
Address:Dubei, Duqiao, Linhai, Taizhou, Zhejiang, China Zip: 317016
Xuzhou Tianrun Chemical Co.,Ltd
website:http://www.tianrunchem.cn
Contact:86-516-83832636
Address:fuxing road
Changsha Nutritopper Bio Technology Co.,Ltd.
Contact:+86-731-87803543
Address:East 1st Street, Baima Road, Ningxiang County
JOY (TIANJIN) TECHNOLOGY AND DEVELOPMENT CO., LTD.
Contact:+86-22-66666666
Address:Tianjin
Shanghai Micro-mega Industry Co., Ltd.
Contact:0086-21-34628682;57153848
Address:Rm413,No.413,West Meilong Road, Minhang District,Shanghai P R China
Doi:10.1021/ja054085l
(2005)Doi:10.1021/ol052128x
(2005)Doi:10.1021/ja003124k
(2001)Doi:10.1007/BF00568269
()Doi:10.1016/S0040-4039(00)88321-5
(1983)Doi:10.1002/recl.19831020505
(1983)