title: Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids.
abstract: In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by the use of X-ray crystallography and circular dichroism. The effects of Pro-Leu-Gly-NH2 analogues 3a-3d and 4a-4d on enhancing rotational behavior induced by apomorphine in the 6-hydroxydopamine-lesioned animal models of Parkinson's disease were studied. The ability of these peptidomimetics to increase the binding of agonist N-propylnorapomorphine (NPA) to the dopamine D2 receptor was also examined. Extended analogue Pro-Leu-Deg-NH2 was the most active compound of this series. It was 10 times more potent and almost 2 times more effective than 1 in increasing apomorphine-induced rotations (56 +/- 15% at 1.0 mg/kg ip) and in enhancing [3H]NPA specific binding (40%).
authors.affiliation: Department of Medicinal Chemistry, The Biomedical Engineering Center, University of Minnesota, Minneapolis, Minnesota 55455-0343, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Pradhan
authors.forename: S
authors.initials: S
authors.lastname: Venkatraman
authors.forename: W H
authors.initials: WH
authors.lastname: Ojala
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; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects
chemical_list: D010455:Peptides; D011954:Receptors, Dopamine; D016627:Oxidopamine; D009075:MSH Release-Inhibiting Hormone