Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D(1), D(2) and serotonin 5-HT(1A) multi-action profile

Haifeng Sun; Liyuan Zhu; Huicui Yang; Wangke Qian; Lin Guo; Shengbin Zhou; Bo Gao; Zeng Li; Yu Zhou; Hualiang Jiang; Kaixian Chen; Xuechu Zhen; Hong Liu

doi:10.1016/j.bmc.2012.12.016

Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D(1), D(2) and serotonin 5-HT(1A) multi-action profile

Bioorg Med Chem. 2013 Feb 15;21(4):856-68. doi: 10.1016/j.bmc.2012.12.016. Epub 2012 Dec 21.

Authors

Haifeng Sun¹, Liyuan Zhu, Huicui Yang, Wangke Qian, Lin Guo, Shengbin Zhou, Bo Gao, Zeng Li, Yu Zhou, Hualiang Jiang, Kaixian Chen, Xuechu Zhen, Hong Liu

Affiliation

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.

PMID: 23332346
DOI: 10.1016/j.bmc.2012.12.016

Abstract

An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D(1), D(2) and serotonin 5-HT(1A) and 5-HT(2A) receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D(1) receptor with K(i) values of 50 and 6.3nM, while both compounds act as D(2) receptor antagonists (K(i)=305 and 145nM, respectively) and 5-HT(1A) receptor full agonists (K(i)=149 and 908nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT(1A) receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.

Publication types

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

MeSH terms

Animals
Antipsychotic Agents / chemical synthesis*
Antipsychotic Agents / pharmacology
Antipsychotic Agents / therapeutic use
Berberine / analogs & derivatives
Berberine / chemistry
Berberine Alkaloids / chemical synthesis
Berberine Alkaloids / chemistry*
CHO Cells
Cricetinae
Cricetulus
Dopamine D2 Receptor Antagonists*
HEK293 Cells
Humans
Microwaves
Motor Activity / drug effects
Protein Binding
Rats
Receptor, Serotonin, 5-HT1A / chemistry*
Receptor, Serotonin, 5-HT1A / metabolism
Receptor, Serotonin, 5-HT2A / chemistry
Receptor, Serotonin, 5-HT2A / metabolism
Receptors, Dopamine D1 / antagonists & inhibitors*
Receptors, Dopamine D1 / metabolism
Receptors, Dopamine D2 / metabolism
Schizophrenia / chemically induced
Schizophrenia / drug therapy
Serotonin 5-HT1 Receptor Agonists / chemistry
Serotonin 5-HT1 Receptor Agonists / pharmacology
Serotonin 5-HT1 Receptor Agonists / therapeutic use
Structure-Activity Relationship

Substances

Antipsychotic Agents
Berberine Alkaloids
Dopamine D2 Receptor Antagonists
Receptor, Serotonin, 5-HT2A
Receptors, Dopamine D1
Receptors, Dopamine D2
Serotonin 5-HT1 Receptor Agonists
Berberine
stepholidine
Receptor, Serotonin, 5-HT1A
protoberberine