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

• Published in: Journal of medicinal chemistry Vol. 40; no. 22; pp. 3594 - 3600
• Main Authors: Baures, Paul W, Ojala, William H, Costain, Willard J, Ott, Michael C, Pradhan, Ashish, Gleason, William B, Mishra, Ram K, Johnson, Rodney L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.1997; Amer Chemical Soc
• Subjects: Animals; Behavior, Animal - drug effects; Biological and medical sciences; Catecholaminergic system; Cattle; Chemistry, Medicinal; Corpus Striatum - drug effects; Diketopiperazines; Dopamine Agents - chemical synthesis; Dopamine Agents - chemistry; Dopamine Agents - pharmacology; Drug Design; In Vitro Techniques; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Medical sciences; Molecular Mimicry; Molecular Structure; MSH Release-Inhibiting Hormone - analogs & derivatives; MSH Release-Inhibiting Hormone - chemical synthesis; MSH Release-Inhibiting Hormone - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperazines - chemistry; Rats; Rats, Sprague-Dawley; Receptors, Dopamine - drug effects; Science & Technology; Spectrometry, Mass, Fast Atom Bombardment; X-Ray Diffraction; CONFORMATIONALLY CONSTRAINED ANALOGS; AFFINITY STATES; L-LEUCYL-GLYCINAMIDE; PLG; PRO-LEU-GLY-NH2; Agonist; Peptides; Rat; Angular nitrogen heterocycle; Lactam; Parkinson disease; Structure activity relation; Modulation; Bicyclic compound; Degenerative disease; Chemical synthesis; Nervous system diseases; Aminoamide; Peptidomimetic compound; Rodentia; Steric hindrance; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; D2 Dopamine receptor; Treatment; Animal; Central nervous system disease; Dipeptides; Affinity; Carboxamide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970328b

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.