Synthesis and Dopamine Receptor Modulating Activity of Lactam Conformationally Constrained Analogues of Pro-Leu-Gly-NH₂

A series of analogues of the potent analogue of Pro-Leu-Gly-NH₂ (PLG), 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide (2) were synthesized in which the (R)-γ-lactam residue of 2 was replaced with a (R)-β-lactam, (R)-aminosuccinimide, (R)-cycloseryl, (R)-δ-lactam, (R)-ϵ-lactam, or (S)-ϵ-lactam residue to give analogues 3–8, respectively. These substitutions were made so as to vary the ψ₂ torsion angle. The analogues were tested for their ability to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor. Analogues 3–6 and 8 exhibited dose-response curves that were bell-shaped in nature with the maximum effect occurring at a concentration of 1 µM. Analogue 7 was inactive. Analogues 3 and 4 were found to be as effective as PLG, while analogues 5, 6, and 8 appeared to be more effective than PLG in terms of enhancing the binding of ADTN to dopamine receptors. The activity of analogues 3–6 and 8 with their ψ₂ angles in the vicinity of that observed in a type II β-turn is consistent with the hypothesis that this type of turn is the bioactive conformation of PLG.