The long-term objective of this research is to gain a better understanding of the way in which the tripeptide L-prolyl-L-leucylglycinamide (PLG) modulates dopamine receptors. In pursuit of this objective, we intend to continue our detailed analysis of the structure-activity relationships of PLG and also to begin studies that hopefully will address the molecular basis for this tripeptide's modulation of dopamine receptors. Specifically, the leucyl residue of PLG will be replaced with L- and D-N-Me-aromatic amino acid residues, while future glycinamide modifications will center around sulfur-containing and olefinic amino acid residues. Bicyclic analogues of PLG that incorporate the thiazolidine-2-carboxamide and Delta-lactam residues within their structure will also be carried out. Analogues of cyclo(leu-gly) will be synthesized to determine in what manner this diketopiperazine resembles PLG in structure. Finally, analogues of the olefinic analogue of PLG Pro-LeuOmega[E-CH=CH]Gly-NH2 will be synthesized in order to explore further the structural features of this peptide analogue that enable it to displace 3H-spiroperidol from its binding sites as well as enhance the binding of dopamine agonists to their receptor. The PLG analogues synthesized will be tested for their ability to enhance the binding of the dopamine agonists ADTN and NPA to dopamine receptors. Analogues with high activity will be evaluated for their ability to displace 3H-PLG from its receptors and to antagonize haloperidol-induced dopamine receptor supersensitivity. The modulatory effects of PLG and its active analogues on D1-dopamine receptors will be investigated using the specific D1-agonist SKF-38393 and D1-antagonist SCH-23390, as will the possible modulatory effect of PLG on agonist-induced """"""""down regulation"""""""" of dopamine receptors. Experiments will be conducted to determine whether PLG's modulation of D1- and D2-receptors is mediated through the interaction of PLG with the guanine nucleotide stimulatory (Gs) on inhibitory (Gi) proteins that are associated with these receptors. Finally, attempts will be made to develop a better radioligand for the PLG-receptor binding assay. These studies should provide us with a better understanding of dopamine receptor modulation, which in turn may shed new light on disease states such as Parkinson's Disease, tardive dyskinesia, schizophrenia, and Gilles de la Tourette syndrome where changes in dopamine receptor sensitivity have been implicated.
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