136247-11-5Relevant academic research and scientific papers
Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A 2A-D2 receptor heteromers
Soriano, Aroa,Ventura, Ruben,Molero, Anabel,Hoen, Rob,Casado, Vicent,Corte, Antoni,Fanelli, Francesca,Albericio, Fernando,Lluís, Carmen,Franco, Rafael,Royo, Miriam
supporting information; experimental part, p. 5590 - 5602 (2010/03/24)
Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease.Here, a family of heterobivalent ligands containing a D2R agonist and an A 2AR antagonist linked through a spacer of variable size was designed and synthesized to study A2AR-D2R heteromers. Bivalent ligands with shorter linkers bound to D2R or A2AR with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A2AR-D2R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A2AR-D2R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.
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.
