Synthesis and dopamine receptor modulating activity of lactam conformationally constrained analogues of Pro-Leu-Gly-NH2.
A series of analogues of the potent analogue of Pro-Leu-Gly-NH2 (PLG), 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacet amide (2) were synthesized in which the (R)-gamma-lactam residue of 2 was replaced with a (R)-beta-lactam, (R)-aminosuccinimide, (R)-cycloseryl, (R)-delta-lactam, (R)-epsilon-lactam, or (S)-epsilon-lactam residue to give analogues 3-8, respectively. These substitutions were made so as to vary the psi 2 torsion angle. The analogues were tested for their ability to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor. Analogues 3-6 and 8 exhibited dose-response curves that were bell-shaped in nature with the maximum effect occurring at a concentration of 1 microM. Analogue 7 was inactive. Analogues 3 and 4 were found to be as effective as PLG, while analogues 5, 6, and 8 appeared to be more effective than PLG in terms of enhancing the binding of ADTN to dopamine receptors. The activity of analogues 3-6 and 8 with their psi 2 angles in the vicinity of that observed in a type II beta-turn is consistent with the hypothesis that this type of turn is the bioactive conformation of PLG.
Sreenivasan
U
U
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Mishra
R K
RK
Johnson
R L
RL
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism
D015259:Dopamine Agents; D007769:Lactams; D009842:Oligopeptides; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C011639:ADTN; C029463:prolyl-lysyl-glycinamide