Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide

In the present study, the synthesis of the 5.5.6. and 5.6.5. spiro bicyclic lactam PLG peptidomimetics, compounds 3 and 4, respectively, was undertake n. These peptidomimetics were designed to examine the following: (1) the ef fect that changing the size of the thiazolidine and lactam ring systems wou ld have on the ability of these systems to mimic the type-II beta-turn and (2) the effect that these structural perturbations would have on the abilit y of the peptidomimetics to modulate dopamine receptors. Through the use of the [H-3]spiroperidol/N-propylnorapomorphine (NPA) dopamine D-2 receptor c ompetitive binding assay, 3 and 4, at a concentration of 100 nM, decreased the dissociation constant of the high-affinity state of the dopamine recept or for the agonist. These effects were observed when either Gpp(NH)p was ab sent or present and they were comparable to those produced by PLG at a conc entration of 1 mu M. Peptidomimetics 3 and 4 also increased the percentage of D-2 receptors that existed in the high-affinity state. Even with Gpp(NH) p present, 3 and 4 were able to return the R-H/R-L ratios to values observe d in the respective controls where Gpp(NH)p was absent. Furthermore, both p eptidomimetics were able to attenuate the Gpp(NH)p-induced shift to the low -affinity state to a greater extent than PLG. Peptidomimetics 3 and 4 were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism, and each a ffected the rotational behavior in a bell-shaped dose-response relationship producing increases of 95 +/- 31% (0.01 mg/kg, ip) and 88 +/- 14% (0.001 m g/kg, ip), respectively. In comparison, the previously reported 5.5.5. spir o bicyclic lactam 2 increased rotational behavior by 25 +/- 11% (0.01 mg/kg , ip).