This competing renewal application will utilize rational drug design to synthesize novel ligands that will be used to understand mechanisms of dopamine receptor function. The directions proposed have, as a foundation, important work done during the previous grant period. The selected targets will have utility in probing specific topographic features of selected dopamine receptor isoforms, will be neuropharmacological tools that will advance the study of the function of dopamine receptors, and may have potential diagnostic or therapeutic uses. A body of work is proposed with the distinct aims: l) to synthesize novel drugs selective for dopamine receptor isoforms; 2) to explore the mechanisms of full intrinsic efficacy at D1-like receptors; and 3) to synthesize drugs to pursue a novel idea we term the """"""""functional selectivity hypothesis."""""""" To develop isoform selective ligands, target molecules are based on a set of structures of known biological activity, in which the proposed structural changes are unlikely to destroy activity. Originally derived from two structural classes designed to be D1 ligands, we hypothesize (based on a large body of previous work) that combinations of substituents on the """"""""accessory hydrophobic region,"""""""" coupled with N-alkylation, will allow us to design drugs that are isoform-selective ligands for the D2, D3, and/or the D4 receptor. The mechanisms of D1-intrinsic activity will be explored using the same two structural backbones, the newer of which is based on a novel molecule named dinapsoline that is a high affinity full D1 agonist from a new structural class. The structural changes we propose parallel those we have made to dihydrexidine, the first full D1 agonist that has profound anti-Parkinson effects. This new backbone will allow us to focus on refining our understanding of the nature and location of the accessory binding region in the D1 receptor, and the role it plays in affecting both D1 selectivity and intrinsic affinity at this receptor. Modifications of the C-ring also will be made, based on the hypothesis that this may lead to the first D5 selective ligand. We shall also continue our efforts to develop radiolabeled high affinity ligands for use as receptor labels. Finally, we shall design drugs that will be used to test the """"""""functional selectivity hypothesis,"""""""" an idea that states that when certain drugs bind to a single receptor isoform the consequent functional changes may differ depending on the character of the associated transduction machinery (i.e., G-protein complement). For all of these aims, essential components are collaborators at the University of North Carolina (UNC) who will conduct the neuropharmacological studies in both brain tissue and molecular expression systems. In addition, molecular modeling and receptor model development will be continued through this collaboration at UNC, using state-of-the-art software techniques to define steric, hydrophobic, and electronic features of the ligand binding domain. Through the design and synthesis of new isoform-selective ligands, and the interdisciplinary collaboration with strong pharmacology and molecular modeling groups, advances in our understanding of dopamine receptor structure and function will occur.
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