Design, synthesis, and evaluation of phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents

Zhaoyang Qi; Ziying Li; Mo Zhu; Xiaohua Zhang; Guisen Zhang; Tao Zhuang; Yin Chen; Ling Huang

doi:10.1016/j.bmcl.2021.128497

Design, synthesis, and evaluation of phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents

Bioorg Med Chem Lett. 2022 Feb 1:57:128497. doi: 10.1016/j.bmcl.2021.128497. Epub 2021 Dec 8.

Authors

Zhaoyang Qi¹, Ziying Li¹, Mo Zhu², Xiaohua Zhang², Guisen Zhang¹, Tao Zhuang³, Yin Chen⁴, Ling Huang⁵

Affiliations

¹ Jiangsu Institute of Marine Resources Development, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang 222005, China.
² Wuhan Docan Pharmaceutical Co., Ltd., Wuhan 430040, China.
³ Jiangsu Institute of Marine Resources Development, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang 222005, China; Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: zhuang_tao@hust.edu.cn.
⁴ Jiangsu Institute of Marine Resources Development, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang 222005, China. Electronic address: 2019000015@jou.edu.cn.
⁵ Jiangsu Institute of Marine Resources Development, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang 222005, China; Wuhan Docan Pharmaceutical Co., Ltd., Wuhan 430040, China. Electronic address: huangcjia@126.com.

PMID: 34896213
DOI: 10.1016/j.bmcl.2021.128497

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 GABA_A 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.

Keywords: Anesthetic; Hypnotic agents; Phenylacetate derivatives; Phenylpiperazine.

MeSH terms

Animals
Drug Design
Guinea Pigs
Hypnotics and Sedatives / chemical synthesis
Hypnotics and Sedatives / metabolism
Hypnotics and Sedatives / pharmacology*
Male
Mice
Phenylacetates / chemical synthesis
Phenylacetates / metabolism
Phenylacetates / pharmacology*
Piperazines / chemical synthesis
Piperazines / metabolism
Piperazines / pharmacology*
Rabbits
Rats
Rats, Sprague-Dawley
Receptors, GABA-A / metabolism

Substances

Hypnotics and Sedatives
Phenylacetates
Piperazines
Receptors, GABA-A