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This study is focused on the identification of structural features that determine the selectivity of dopamine receptor agonists toward D1 and D2 receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor (the Ser residues in TM5 and the Asp in TM3), a directional aromatic feature in the ligand, a feature with large positional tolerance representing the positively charged nitrogen in the ligand, and sets of excluded volumes reflecting the shapes of the receptors. The sets of D1 and D2 ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. The robustness of the models in discriminating actives from inactives was tested against four ensembles of conformations generated by using different established methods and different force fields. The reasons for the selectivity can be attributed to both geometrical differences in the arrangement of the features, e.g., different tilt angels of the π system, as well as shape differences covered by the different sets of excluded volumes. This work provides useful information for the design of new D1 and D2 agonists and also for comparative homology modeling of D1 and D2 receptors. The approach is general and could therefore be applied to other ligand–protein interactions for which no experimental protein structure is available. 相似文献
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Dr. Mingcheng Qian Kuo Zhou Yi Wu Zhijie Luo Zhekai Xiao Jingjing Sun Siyu Zeng Yi Yao Dr. Shuai Zhao Prof. Xin Chen 《ChemMedChem》2022,17(4):e202100681
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. 相似文献
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Dr. Jeremy Murray Dr. Anthony M. Giannetti Micah Steffek Paul Gibbons Dr. Brian R. Hearn Dr. Frederick Cohen Christine Tam Christine Pozniak Brandon Bravo Dr. Joe Lewcock Priyadarshini Jaishankar Cuong Q. Ly Xianrui Zhao Dr. Yinyan Tang Dr. Preeti Chugha Prof. Michelle R. Arkin Dr. John Flygare Prof. Adam R. Renslo 《ChemMedChem》2014,9(1):2-2
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Claudia Pessoa Dr. Paulo Michel P. Ferreira Letícia Veras C. Lotufo Dr. Manoel O. de Moraes Prof. Suellen M. T. Cavalcanti Lucas Cunha D. Coêlho Marcelo Z. Hernandes Dr. Ana Cristina L. Leite Prof. Carlos A. De Simone Dr. Vlaudia M. A. Costa Dr. Valdênia M. O. Souza Dr. 《ChemMedChem》2010,5(4):486-486
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Cover Picture: Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors (ChemMedChem 1/2014)
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Dr. Mathew P. Leese Dr. Fabrice L. Jourdan Dr. Meriel R. Major Dr. Wolfgang Dohle Dr. Ernest Hamel Dr. Eric Ferrandis Dr. Ann Fiore Dr. Philip G. Kasprzyk Prof. Barry V. L. Potter 《ChemMedChem》2014,9(1):1-1