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

Ling Huang; Wenjun Zhang; Xiaohua Zhang; Lei Yin; Bangyin Chen; Jinchun Song

doi:10.1016/j.bmcl.2015.09.045

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

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5299-305. doi: 10.1016/j.bmcl.2015.09.045. Epub 2015 Sep 21.

Authors

Ling Huang¹, Wenjun Zhang², Xiaohua Zhang², Lei Yin², Bangyin Chen³, Jinchun Song⁴

Affiliations

¹ Wuhan Docan Pharmaceutical Co., Ltd, Wuhan 430040, China; Pharmacy School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Wuhan Docan Pharmaceutical Co., Ltd, Wuhan 430040, China.
³ Pharmacy School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁴ Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: songjcwhu@163.com.

PMID: 26483200
DOI: 10.1016/j.bmcl.2015.09.045

Abstract

The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.

Keywords: Antipsychotic; Benzoxazole; Piperazine; Piperidine.

MeSH terms

Animals
Antipsychotic Agents / chemical synthesis*
Antipsychotic Agents / pharmacology
Antipsychotic Agents / toxicity
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Humans
Mice
Oxazoles / chemical synthesis*
Oxazoles / pharmacology
Oxazoles / toxicity
Patch-Clamp Techniques
Piperazines / chemical synthesis*
Piperazines / pharmacology
Piperazines / toxicity
Piperidines / chemical synthesis*
Piperidines / pharmacology
Piperidines / toxicity
Potassium Channel Blockers / chemical synthesis
Potassium Channel Blockers / pharmacology
Potassium Channel Blockers / toxicity
Rats
Receptors, Dopamine D2 / agonists
Schizophrenia / drug therapy*
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
Serotonin 5-HT1 Receptor Agonists / pharmacology
Serotonin 5-HT1 Receptor Agonists / toxicity
Serotonin 5-HT2 Receptor Agonists / chemical synthesis
Serotonin 5-HT2 Receptor Agonists / pharmacology
Serotonin 5-HT2 Receptor Agonists / toxicity
Structure-Activity Relationship
Swine

Substances

3-(1-(3-(4-(benzo(d)oxazol-2-ylmethyl)phenoxy)propyl)piperidin-4-yl)-6-fluorobenzo(d)isoxazole
Antipsychotic Agents
Ether-A-Go-Go Potassium Channels
KCNH1 protein, human
Oxazoles
Piperazines
Piperidines
Potassium Channel Blockers
Receptors, Dopamine D2
Serotonin 5-HT1 Receptor Agonists
Serotonin 5-HT2 Receptor Agonists