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

In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a- 3d and 4a-4d were synthesized utilizing alpha,alpha-disubstituted amino aci ds. These analogues were designed to explore the conformational effects of constraints at the phi(3) and psi(3) torsion angles. Constrained conformati ons were verified by the use of X-ray crystallography and circular dichrois m. The effects of Pro-Leu-Gly-NH2 analogues 3a-3d and 4a-4d on enhancing ro tational behavior induced by apomorphine in the 6-hydroxydopamine-lesioned animal models of Parkinson's disease were studied. The ability of these pep tidomimetics to increase the binding of agonist N-propylnorapomorphine (NPA ) to the dopamine D-2 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-i nduced rotations (56 +/- 15% at 1.0 mg/kg ip) and in enhancing [H-3]NPA spe cific binding (40%).