This research seeks to develop an understanding of the factors involved in ligand recognition by dopamine receptors, and the functional consequences of such interactions. New drugs, one product of these efforts, will be used to develop an better understanding of the functional consequences of dopamine receptor occupation in both model in vitro systems, and the mammalian nervous system. To do this we shall characterize antagonist ligand interactions with sub-populations of D1-like dopamine receptors, and develop new subclass selective antagonists. Molecular modeling studies, combined with selected syntheses, will help elucidate the structural features that give ligands potency for D1-like receptors, and lend antagonist characteristics to them. These studies will test specific hypotheses about the pharmacophore for D1 -like receptors in 3D space, with an initial focus on rigid compounds in which the """"""""accessory aromatic"""""""" system is in the orthogonal configuration we hypothesize is important for antagonist activity at D1-like (e.g., D1 and D5) receptors. Biological data from both brain preparations and molecular expression systems will provide the input data for quantitative structure and activity studies based on computerized molecular modeling. The mechanism(s) and functional consequences of our full agonist dihydrexidine (DHX) will be compared to available partial or complex agonists (e.g., SKF 38393 or SKF 82958). The factors that mediate desensitization will be studied using clonal cell lines and stable expression systems. Hypotheses from such -work will be tested in more complex systems, using both in vitro (e.g., slice perfusion) and in vivo (e.g., behavioral and microdialysis) techniques. Additional efforts will be aimed at developing and characterizing bioavailable prodrugs of DHX (e.g., methylenedioxyDHX) or its analogs. Finally, we shall design and synthesize D1-like ligands that are """"""""biodetectable"""""""". This will include synthesizing and characterizing radiolabeled derivatives of specifically interesting drugs (initially 3H-DHX), and also to design and synthesize fluorescent D1-ligands. Finally, Although the focus of our work has been on D1-like receptors, serendipitous findings have led to a second focus on D2 like (e.g., D2, D3, D4) receptors. Based on recent preliminary data, we shall determine if certain tetrahydrobenzophenanthridine derivatives have selectivity for D2-like post-synaptic receptors. This will involve in vitro and in vivo studies using mammalian preparations, and later, examining these drugs in systems expressing only one molecular form of this class of receptors.
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