Synthesis of Bitopic Ligands as Potent Dopamine D2 Receptor Agonists |
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Authors: | Dr. Mingcheng Qian Kuo Zhou Yi Wu Zhijie Luo Zhekai Xiao Jingjing Sun Siyu Zeng Yi Yao Dr. Shuai Zhao Prof. Xin Chen |
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Affiliation: | School of Pharmacy, Changzhou University, Changzhou, 213164 P. R. China |
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Abstract: | In this study, we designed and synthesized twelve bitopic ligands as dopamine D2 receptor (D2R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D2R. Furthermore, bitopic ligand N-((trans)-4-(((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclo-hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide ( 11 b ) showed 21-fold higher potency than lead compound propyl aminoindane ( 2 ) and 17-fold higher subtype selectivity for D2R over D4R, indicating that the optimal length of spacer affects the D2R functionality. Molecular modeling study exhibited that 11 b formed an electrostatic interaction and two H-bonds with amino acid Asp114, which contributes significantly to the D2R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D2R agonist, which may be used as a tool compound for further study. |
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Keywords: | dopamine D2 receptor bitopic ligands D2R agonists subtype selectivity |
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