Synthesis and Dopamine Receptor Modulating Activity of Novel Peptidomimetics of l-Prolyl-l-leucyl-glycinamide Featuring α,α-Disubstituted Amino Acids
journal contributionposted on 20.03.1999 by Margaret C. Evans, Ashish Pradhan, Shankar Venkatraman, William H. Ojala, William B. Gleason, Ram K. Mishra, Rodney L. Johnson
Any type of content formally published in an academic journal, usually following a peer-review process.
In the present study, l-prolyl-l-leucyl-glycinamide (1) peptidomimetics 3a−3d and 4a−4d were synthesized utilizing α,α-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the φ3 and ψ3 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%).