This application requests continued support of our drug design efforts aimed both at novel ligands that are dopamine receptor (DAR) isoform-selective agonists, and that can be used as tools to probe the structure and function of this subfamily of GPCRs. Although we are one of the few academic laboratories in the world actively pursuing these lines of research, this project has had a long and successful history in the design and synthesis of dopamine D1/D5 agonists, and their use in understanding DAR function. The design and synthesis efforts supported by this work occur in the context of an independently funded long-term collaboration that provides important pharmacological and computational input. One direction to be pursued is synthesis and characterization of new molecules that will permit the development of a body of data that would lead to the design of agonists selective for the D5, the D1, or both isoforms. These are classes of drugs that do not currently exist, but for which there would be exquisite research and even clinical utility. Full efficacy dopamine D1/D5 agonists are starting to be recognized for their potential as the most effective therapeutic agents for the treatment of mid- and late stage Parkinson's disease, and there is now good evidence that such agonists may also be useful in treating cognitive deficits induced by certain neuroleptics, improving memory, in reversing the negative symptoms of schizophrenia, etc. The approach to be employed is driven by medicinal chemistry and proposes the synthesis of structural modifications that focus on the B-phenyl-B-dopamine pharmacophore that we have identified and used as a template with outstanding success. We have produced three structurally diverse dopamine agonists from this template, and all of them have shown remarkable efficacy vs MPTP-parkinsonism in nonhuman primates. This work provides a foundation for molecular exploitation that will lead to additional important compounds. These will define structure-activity relationships that will help to define the nature of the binding domains necessary to activate the target dopamine receptors. We shall also follow-up on substantial improvements in pharmacokinetic properties we have made without sacrificing desired pharmacodynamic characteristics. The products of this work have a high likelihood of significant impact on basic studies of receptor function, and on the therapy of numerous CNS disorders.
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