| Autor: |
Baures, P. W., Ojala, W. H., Costain, W. J., Ott, M. C., Pradhan, A., Gleason, W. B., Mishra, R. K., Johnson, R. L. |
| Zdroj: |
Journal of Medicinal Chemistry; October 24, 1997, Vol. 40 Issue: 22 p3594-3600, 7p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
