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 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 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 behavior in a dose-dependent manner. The maximum effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 +/- 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.
Baures
P W
PW
Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455, USA.
Ojala
W H
WH
Costain
W J
WJ
Ott
M C
MC
Pradhan
A
A
Gleason
W B
WB
Mishra
R K
RK
Johnson
R L
RL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002417:Cattle; D003342:Corpus Striatum / Q000187:drug effects; D054659:Diketopiperazines; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D066298:In Vitro Techniques; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018716:Molecular Mimicry; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014961:X-Ray Diffraction
D054659:Diketopiperazines; D015259:Dopamine Agents; D010879:Piperazines; D011954:Receptors, Dopamine; D009075:MSH Release-Inhibiting Hormone