Design, synthesis, and evaluation of phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. (1st February 2022)

• Record Type: Journal Article
• Authors: Qi, Zhaoyang; Li, Ziying; Zhu, Mo; Zhang, Xiaohua; Zhang, Guisen; Zhuang, Tao; Chen, Yin; Huang, Ling
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 57(2022)
• Publication Date: 2022-02-01
• Subjects: Anesthetic -- Phenylpiperazine -- Phenylacetate derivatives -- Hypnotic agents; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128497
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Eighteen phenylpiperazine-phenylacetate derivatives with hypnotic potencies were synthesized. Compound 10 showed apparently rapid recovery and higher safety than propanidid in animal models. Compound 10 had a greater binding affinity for the GABAA receptor and a lower affinity for the off-target receptors. Abstract: In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABAA receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD50 = 5.2 mg/kg in rabbits), comparable duration of the loss of righting reflex (LORR), and significant shorter recovery time (time to walk) than propanidid. Furthermore, compound 10 (TI = 18.1) showed higher safety profile than propanidid (TI = 14.7) in rabbits. Above results suggested that compound 10 may have predictable and rapid recovery profile in anesthesia.