Bicyclic Thiazolidine Lactam Peptidomimetics of the Dopamine Receptor Modulating Peptide Pro-Leu-Gly-NH₂

Bicyclic thiazolidine lactam peptidomimetics 3–5 have been synthesized as potential analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH₂ (PLG). Peptidomimetics 3 and 4 were designed to constrain two, ψ₂ and ϕ₃, of the four torsion angles that define a β-turn to values approximating those found for a type-II β-turn, while 5 was designed as a compound that could not achieve a β-turn conformation. Peptidomimetics 3 and 4 were found to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while 5 was found to be inactive. Like PLG the dose-response curves for 3 and 4 were bell-shaped in nature with the maximum effect occurring at a concentration of 1 µM. Both 3 and 4 were more effective than PLG in enhancing the binding of ADTN to dopamine receptors. The 5,5-bicyclic thiazolidine lactam peptidomimetic 3 enhanced the binding of ADTN by almost 200%, while the 6,5-bicyclic thiazolidine lactam peptidomimetic 4 enhanced the binding of ADTN by about 75%. These results provide further evidence in support of the hypothesis that the bioactive conformation of PLG is a type-II β-turn.