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 |
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| Institution: | 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;1. Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty and Graduate School of Sciences, Risk Science Research Center, Kyushu University, Fukuoka 812-8581, Japan;2. Laboratorio di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, Roma, Italy;1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China;2. Institute of Functional Molecules, Shenyang University of Chemical Technology, Shenyang, Liaoning, 110142, PR China;3. Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China;1. Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece;2. Pharmathen SA – R&D API Operations, 9th km Thermi-Thessaloniki, Thessaloniki 57001, Greece |
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| 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 23e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23d and 23e were more potent than l-SPD at D3 receptor. According to the functional assays, 23d and 23e 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. |
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| Keywords: | Tetrahydroprotoberberine Dopamine receptor Serotonin receptor Multiple action |
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