Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity |
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| Institution: | 1. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA;2. Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA;3. Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA;4. Department of Chemistry, Lehman College, The City University of New York, Bronx, NY 10468, USA;5. Department of Natural Sciences, LaGuardia Community College, City University of New York, New York, NY 11101, USA;6. Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji’nan, Shandong 250012, China;2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;3. Institute of Criminal Science and Technology, Ji’nan Public Security Bureau, Ji’nan 250100, China;4. School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, China;1. Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic;2. Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic;3. Department of Organic Chemistry, Faculty of Science, Pavol Jozef Šafárik University, Moyzesova 11, 041 01 Košice, Slovak Republic;4. Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava, Slovak Republic;5. Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovak Republic;1. State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, PR China;2. Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, PR China;3. Ningbo Dongmi Pharmaceutical Co., Ltd, Ningbo 315899, Zhejiang, PR China;4. Shanghai Xianhui Pharmaceutical Co., Ltd, Shanghai 200433, PR China |
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| Abstract: | Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds. |
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| Keywords: | Dopamine Sigma D3 Tetrahydroprotoberberine THPB Stepholidine |
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