Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 1997-10, Vol.40 (22), p.3594-3600

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

1997

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.