title: Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Baures
authors.forename: W H
authors.initials: WH
authors.lastname: Ojala
authors.forename: W J
authors.initials: WJ
authors.lastname: Costain
authors.forename: M C
authors.initials: MC
authors.lastname: Ott
authors.forename: A
authors.initials: A
authors.lastname: Pradhan
authors.forename: W B
authors.initials: WB
authors.lastname: Gleason
authors.forename: R K
authors.initials: RK
authors.lastname: Mishra
authors.forename: R L
authors.initials: RL
authors.lastname: Johnson
mesh_terms: 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
chemical_list: D054659:Diketopiperazines; D015259:Dopamine Agents; D010879:Piperazines; D011954:Receptors, Dopamine; D009075:MSH Release-Inhibiting Hormone