The long term objective of the proposed research is to gain a better understanding of the way in which L-Prolyl-L-Leucylglycinamide (PLG) modulates the sensitivity of dopamine receptors within the central nervous system. In pursuit of this objective, we intend to carry out a detailed analysis of the structural features of PLG that enable this tripeptide to modulate dopamine receptor sensitivity. A series of analogues of PLG will be synthesized wherein each of the three amino acid residues of this tripeptide will be systematically modified. A second series of conformationally constrained analogues of PLG will be synthesized in order to obtain information about the biologically active conformation of this tripeptide. The PLG analogues will be tested for their ability to bind to the putative PLG receptor using a radioligand binding assay. The PLG analogues will also be tested for their ability to enhance apomorphine binding to dopamine receptors and to antagonize neuroleptic drug enhancement of specific 3H-spiroperidol binding. Finally, the ability of the PLG analogues to antagonize neuroleptic drug-induced catalepsy will also be measured. It is felt that the proposed study will not only provide us with a better understanding of dopamine receptor modulation, but will also yield potential pharmacological tools which could further help elucidate the mechanism of the phenomenon. This in turn may lead to a better understanding of neurological disorders such as Parkinson's Disease, tardive dyskinesia, schizophrenia, Gilles de la Tourette syndrome, and opiate tolerance and physical dependence in which changes in central dopamine receptor sensitivity have been implicated.
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