DESIGN, SYNTHESIS, AND DOPAMINE-RECEPTOR MODULATING ACTIVITY OF DIKETOPIPERAZINE PEPTIDOMIMETICS OF L-PROLYL-L-LEUCYLGLYCINAMIDE

The diketopiperazine ''C5'' conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG,1) structure and into the bicyclic lactam PLG peptidomimetic structure 3 to give compounds 5 and 6, respectively. These analogues were designed to explore the idea th at the N-terminal ''C5'' conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine fun ction, was a factor in the high potency of these two agents. Through t he use of the [H-3]spiroperidol/N-propylnorapomorphine (NPA) D-2 recep tor competitive binding assay, both 5 and 6 were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D-2 receptors which existed in the high-af finity state. These effects were observed when Gpp(NH)p was either abs ent or present, and they were analogous to the effects observed previo usly for PLG and the PLG peptidomimetics 2 and 4. However, the potency seen with 5 and 6 was less than that seen for 2 and 4, suggesting tha t while the N-terminal ''C5'' conformation may play a role in the pote ncy of the gamma-lactam peptidomimetics of PLG, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, 5 altered apomorphine-induced rotational behav ior in a dose-dependent manner. The maximum effect occurred at a dose of 0.01 mg/kg ip and resulted in a 52.27 +/- 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.