PRO-LEU-GLY-NH2 AND DOPAMINE RECEPTOR MODULATION

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The long term objective of this research is to gain a better understanding of the way in which Pro-Leu-Gly-NH2 (PLG) modulates dopamine receptors. Detailed analysis of the structure/conformation-activity relationships of our highly potent lactam analogue 3(R)-(N-L-prolyl)amino-2-oxo-1- pyrrolidineacetamide (3) will be carried out whereby the prolyl residue and lactam ring are modified and the 3-position of the lactam ring and the alpha-carbon of the acetamide portion of the molecule are substituted. Modifications of our highly effective bicyclic thiazolidine lactam 14 will be made and novel peptide mimics in which various phi and psi torsional angles are restricted through multiple conformational constraints will be synthesized. The compounds synthesized will be tested for their ability to enhance the binding of dopamine receptor agonists to D1- and D2-dopamine receptors using either bovine caudate, cultured cell lines, or purified preparations of D1- and D2-receptors. The analogues will also be evaluated for their ability to displace 3H-PLG from the putative PLG receptor. Selected analogues will be tested for their ability to antagonize haloperidol (D2)- and SCH 23390 (D1)-induced dopamine receptor supersensitivity, to affect 6-hydroxydopamine-induced DA supersensitivity, and to modulate agonist induced down-regulation of dopamine receptors. Autoradiography will be used to investigate the interaction of PLG analogues with dopamine at the D1 receptor at various levels of the striatum. The effect of PLG and its analogues on D1 and D2 receptor mRNA expression will be investigated. Further investigations into the interaction of PLG with the guanine nucleotide stimulatory or inhibitory proteins will be undertaken by determining the effect of PLG and its analogues on: (a) dopamine agonist-induced stimulation of high-affinity GTPase activity in membranes; (b) adenylate cyclase inhibition/activation by dopamine agonists; and (c) G-protein (Gi, Gs and Go) levels and their corresponding mRNA levels. These studies should provide us with a better understanding of dopamine receptor modulation which in turn should increase our understanding of such disease states as Parkinson's disease, tardive dyskinesia and schizophrenia where changes in dopamine receptor sensitivity have been implicated.