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Design, Synthesis, and Dopamine Receptor Modulating Activity of Diketopiperazine Peptidomimetics of l-Prolyl-l-leucylglycinamide

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journal contribution
posted on 24.10.1997, 00:00 authored by Paul W. Baures, William H. Ojala, Willard J. Costain, Michael C. Ott, Ashish Pradhan, William B. Gleason, Ram K. Mishra, Rodney L. Johnson
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 peptidomimetics 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.

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