This proposal would continue our longstanding efforts to explore the structure-activity relationships of novel full agonists for the human dopamine D1 receptor. Our past success exploiting the """"""""beta-phenyldopamine"""""""" pharmacophore will continue to guide our design efforts for new ligands. Novel ligands to be examined should provide molecular probes not only of the D1/D5 receptors, but also for all of the other dopamine receptor isoforms. The research proposed in this application has three specific aims. First, we seek to expand and develop structure-activity relationships for a new type of DI full agonist that we have just discovered. Second, we propose the synthesis and evaluation of a focused library of small molecules as potential bioisosteres of the catechol function that might lead to an orally-available, noncatechol dopamine DI agonist. Finally, the third aim presents the synthesis of a number of novel ligands that are anticipated to possess dopamine agonist activity. All new ligands will be screened for affinity and functional activity at all five dopamine receptor isoforms. In addition, the data will be used to refine further homology models of the DI and D2 receptors so as to gain a better understanding of the structural features necessary to confer agonist activity and selectivity onto dopaminergic ligands. This model ultimately will be used in structure-based molecule design efforts, as well as to help understand how ligand structure affects receptor function. This work is of particular importance to the mission of NIMH, as the dopamine D1 receptor has been implicated in a number of CNS disorders, including cognitive and memory deficits in schizophrenia. In addition, all of the ligands that we have developed, and propose to develop here, can be custom-tailored by specific structural modifications to provide ligands with a mix of effects at the various dopamine receptor isoforms. Thus, these ligands represent novel molecular probes for dopamine receptors, as well as being potential new therapies for CNS disorders that involve dysfunction in dopamine pathways. ? ? Dopamine is a critical neurotransmitter in brain areas involved in mood regulation, drug addiction, movement disorders, and memory and cognition, among others. Our work will generate molecular probes that should help to increase our understanding of these pathways, and may also provide new therapies for disorders such as Parkinson's disease and schizophrenia. ? ? ?
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