Dopamine Receptor Modulation by a Highly Rigid Spiro Bicyclic Peptidomimetic of Pro-Leu-Gly-NH₂

A peptidomimetic analogue of Pro-Leu-Gly-NH₂ (PLG), compound 3, has been synthesized that contains a highly constrained spiro bicyclic type-II β-turn mimic. Peptidomimetic 3 enhanced the binding of the dopamine receptor agonist ADTN to dopamine receptors by 40% at 10⁻⁶ M. At this same concentration PLG enhanced the binding of ADTN by 26%. Like PLG, 3 exhibited a bell-shaped dose-response curve with the maximum effect occurring at a concentration of 10⁻⁶ M. Because of the highly rigid nature of the spiro bicyclic type-II β-turn constraint found in 3, these results lend strong support for the hypothesis that the biologically active conformation of PLG is a type-II β-turn.