Synthesis and dopamine receptor modulating activity of substituted bicyclic thiazolidine lactam peptidomimetics of L-prolyl-L-leucyl-glycinamide

6-Substituted bicyclic thiazolidine lactam peptidomimetics of Pro-Leu-Gly-N H2 (1) were synthesized to test the hypothesis that incorporation of a hydr ophobic side chain into the bicyclic thiazolidine lactam scaffold would fur ther enhance the dopamine receptor modulating activity of such peptidomimet ics. The substituents employed were the isobutyl, butyl, and benzyl groups to give peptidomimetics 3-5, respectively. These peptidomimetics were evalu ated in vivo as modulators of apomorphine-induced rotational behavior in th e 6-hydroxydopamine-lesioned rat model of hemiparkinsonism and were compare d with the unsubstituted bicyclic thiazolidine lactam Pro-Leu-Gly-NH2 pepti domimetic 2. Peptidomimetics 3-5 each affected rotational behavior in a bel l-shaped dose-response relationship producing maximal increases of 44% (1 m u g/kg, ip), 56% (0.1 mu g/kg, ip), and 30% (1 mu g/kg, ip), respectively. In comparison, unsubstituted peptidomimetic 2 increased rotational behavior by only 23% at a dose of 0.1 mu g/kg, ip.