Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l-SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles

Zeng Li; Jiye Huang; Haifeng Sun; Shengbin Zhou; Lin Guo; Yu Zhou; Xuechu Zhen; Hong Liu

doi:10.1016/j.bmc.2014.09.024

Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l-SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles

Bioorg Med Chem. 2014 Nov 1;22(21):5838-46. doi: 10.1016/j.bmc.2014.09.024. Epub 2014 Sep 19.

Authors

Zeng Li¹, Jiye Huang², Haifeng Sun¹, Shengbin Zhou¹, Lin Guo³, Yu Zhou¹, Xuechu Zhen⁴, Hong Liu⁵

Affiliations

¹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
² Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
³ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
⁴ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, PR China; Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address: zhenxuechu@suda.edu.cn.
⁵ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address: hliu@mail.shcnc.ac.cn.

PMID: 25308766
DOI: 10.1016/j.bmc.2014.09.024

Abstract

A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5-HT2A) receptors. Most of the tetracyclic compounds exhibited higher affinities for D2 and 5-HT1A receptors than l-SPD, while compound 23 e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23 d and 23 e were more potent than l-SPD at D3 receptor. According to the functional assays, 23 d and 23 e were demonstrated as full antagonists at D1 and D2 receptors and full agonists at 5-HT1A receptor. Since the combination of D2 antagonism and 5-HT1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents.

Keywords: Dopamine receptor; Multiple action; Serotonin receptor; Tetrahydroprotoberberine; l-SPD.

Publication types

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

MeSH terms

Antipsychotic Agents / chemical synthesis*
Antipsychotic Agents / chemistry
Antipsychotic Agents / metabolism
Antipsychotic Agents / pharmacology
Binding Sites
Dopamine Agonists / chemical synthesis
Dopamine Agonists / chemistry
Dopamine Agonists / metabolism
Dopamine Agonists / pharmacology
Dopamine Antagonists / chemical synthesis
Dopamine Antagonists / chemistry
Dopamine Antagonists / metabolism
Dopamine Antagonists / pharmacology
Drug Design*
Humans
Molecular Docking Simulation
Protein Binding / drug effects
Protein Structure, Tertiary
Quinolizines / chemical synthesis
Quinolizines / chemistry*
Quinolizines / metabolism
Quinolizines / pharmacology
Receptor, Serotonin, 5-HT1A / chemistry
Receptor, Serotonin, 5-HT1A / metabolism*
Receptor, Serotonin, 5-HT2A / chemistry
Receptor, Serotonin, 5-HT2A / metabolism
Receptors, Dopamine D1 / chemistry
Receptors, Dopamine D1 / metabolism*
Receptors, Dopamine D2 / chemistry
Receptors, Dopamine D2 / metabolism*
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
Serotonin 5-HT1 Receptor Agonists / chemistry
Serotonin 5-HT1 Receptor Agonists / metabolism
Serotonin 5-HT1 Receptor Agonists / pharmacology
Structure-Activity Relationship

Substances

Antipsychotic Agents
Dopamine Agonists
Dopamine Antagonists
Quinolizines
Receptor, Serotonin, 5-HT2A
Receptors, Dopamine D1
Receptors, Dopamine D2
Serotonin 5-HT1 Receptor Agonists
Receptor, Serotonin, 5-HT1A