Two series of conformationally constrained analogues of Pro-Leu-Gly-NH2 (PLG) have been synthesized. In one series of analogues, the Leu-Gly-NH2 dipeptide segment of PLG was replaced with the γ-lactam residues 3(S)-and 3(R)-amino-2-oxopyrrolidineacetamide and the γ-lactam residue 3(S)-amino-2-oxopiperidineacetamide. The corresponding γ-lactam analogues of <Glu-Leu-Gly-NH2 were also synthesized. In a second series of analogues, the glycinamide residue of PLG was replaced with the 2-ketopiperazine, 3(S)-amino-2-pyrrolidone, and 3(S)-amino-2-piperidone residues. The above analogues were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Of the conformationally constrained analogues of PLG synthesized in this study, only the γ-lactam analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide (3) was found to possess significant activity. This analogue was 10000 times more active than PLG, under preincubation conditions. It significantly enhanced the binding of ADTN at concentrations of 10-9 and 10-10 M.