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Synthesis and Dopamine Receptor Modulating Activity of Novel Peptidomimetics of l-Prolyl-l-leucyl-glycinamide Featuring α,α-Disubstituted Amino Acids

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posted on 20.03.1999 by Margaret C. Evans, Ashish Pradhan, Shankar Venkatraman, William H. Ojala, William B. Gleason, Ram K. Mishra, Rodney L. Johnson
In the present study, l-prolyl-l-leucyl-glycinamide (1) peptidomimetics 3a3d and 4a4d 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 3a3d and 4a4d 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%).

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