Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide

Paul W. Baures, William H. Ojalar, Willard J. Costain, Michael C. Ott, Ashish Pradhan, William B. Gleason, Ram K. Mishra, Rodney L. Johnson

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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 that the N- terminal 'C5' conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N- propylnorapomorphine (NPA) D2 receptor 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 D2 receptors which existed in the high-affinity state. These effects were observed when Gpp(NH)p was either absent or present, and they were analogous to the effects observed previously for PLG and the PLG peptidemimetics 2 and 4. However, the potency seen with 5 and 6 was less than that seen for 2 and 4, suggesting that while the N-terminal 'C5' conformation may play a role in the potency of the γ- 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 behavior 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.

Original languageEnglish (US)
Pages (from-to)3594-3600
Number of pages7
JournalJournal of medicinal chemistry
Issue number22
StatePublished - 1997


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