136247-26-2Relevant academic research and scientific papers
Design, synthesis and biological evaluation of bivalent ligands against A 1-D 1 receptor heteromers
Shen, Jian,Zhang, Lei,Song, Wan-Ling,Meng, Tao,Wang, Xin,Chen, Lin,Feng, Lin-Yin,Xu, Ye-Chun,Shen, Jing-Kang
, p. 441 - 452 (2013/08/25)
Aim:To design and synthesize bivalent ligands for adenosine A 1-dopamine D 1 receptor heteromers (A 1-D 1 R), and evaluate their pharmacological activities.Methods:Bivalent ligands and their corresponding A 1 R monovalent ligands were designed and synthesized. The affinities of the bivalent ligands for A 1 R and D 1 R in rat brain membrane preparation were examined using radiolabeled binding assays. To demonstrate the formation of A 1-D 1 R, fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D 1-CFP and A 1-YFP. Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions.Results:Two bivalent ligands for A 1 R and D 1 R (20a, 20b), as well as the corresponding A 1 R monovalent ligands (21a, 21b) were synthesized. In radiolabeled binding assays, the bivalent ligands showed affinities for A 1 R 10-100 times higher than those of the corresponding monovalent ligands. In FRET experiments, the bivalent ligands significantly increased the heterodimerization of A1R and D 1 R compared with the corresponding monovalent ligands. A heterodimer model with the interface of helixes 3, 4, 5 of A1R and helixes 1, 6, 7 from D 1 R was established with molecular modeling. The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 ?, which was shorter than the length of the bivalent ligands.Conclusion:This study demonstrates the existence of A 1-D 1 R in situ and a simultaneous interaction of bivalent ligands with both the receptors.
Fluorescent Probes for Dopamine Receptors: Synthesis and Characterization of Fluorescein and 7-Nitrobenz-2-oxa-1,3-diazol-4-yl Conjugates of D-1 and D-2 Receptor Ligands
Bakthavachalam, Venkatesalu,Baindur, Nandkishore,Madras, Bertha K.,Neumeyer, John L.
, p. 3235 - 3241 (2007/10/02)
Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors.Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl)derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace SCH 23390 and 3H)spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis).The fluorescein derivatives of PPHT andSKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of parent ligands.The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands.The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues.In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor.These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively.The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
