Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics

Ling Huang; Lanchang Gao; Xiaohua Zhang; Lei Yin; Jintao Hu; Ting Song; Yin Chen

doi:10.1016/j.bmcl.2020.127506

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127506. doi: 10.1016/j.bmcl.2020.127506. Epub 2020 Aug 20.

Authors

Ling Huang¹, Lanchang Gao², Xiaohua Zhang³, Lei Yin³, Jintao Hu³, Ting Song³, Yin Chen⁴

Affiliations

¹ Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; Wuhan Docan Pharmaceutical Co., Ltd., Wuhan 430040, China.
² Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
³ Wuhan Docan Pharmaceutical Co., Ltd., Wuhan 430040, China.
⁴ Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China. Electronic address: 2019000015@jou.edu.cn.

PMID: 32828898
DOI: 10.1016/j.bmcl.2020.127506

Abstract

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D₂, 5-HT_1A, and 5-HT_2A receptors, but low affinity for the 5-HT_2C and histamine H₁ receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.

Keywords: Amide; Antipsychotic; Multi-target; Piperazine; Piperidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology*
Dose-Response Relationship, Drug
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Ligands
Molecular Structure
Piperazine / chemical synthesis
Piperazine / chemistry
Piperazine / pharmacology*
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Rats
Receptors, Dopamine D2 / metabolism
Receptors, Serotonin / metabolism
Schizophrenia / drug therapy*
Schizophrenia / metabolism
Structure-Activity Relationship

Substances

Amides
Antipsychotic Agents
Ether-A-Go-Go Potassium Channels
Ligands
Piperidines
Receptors, Dopamine D2
Receptors, Serotonin
Piperazine
piperidine