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

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.

Author information

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.

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

PMID:
25308766
DOI:
10.1016/j.bmc.2014.09.024
[Indexed for MEDLINE]

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