Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring α, α-disubstituted amino acids

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 o 3 and ψ 3 torsion angles. Constrained conformations were verified by the use of X-ray crystallography and circular dichroism. The effects of Pro-Leu-Gly-NH 2 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 D 2 receptor was also examined. Extended analogue Pro-Leu-Deg-NH 2 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 [ 3 H]NPA specific binding (40%).