Synthesis and Biological Evaluation of Analogues of Pro-Leu-Gly-NH₂ Modified at the Leucyl Residue

A series of analogues of Pro-Leu-Gly-NH₂ (PLG) in which the leucine residue has been replaced with the aliphatic amino acids L-isoleucine, L-2-aminohexanoic acid (Ahx), L-2-aminopentanoic acid, and L-2-aminobutanoic acid and the aromatic amino acids L-phenylalanine, L-phenylglycine, L- and D-2-amino-4-phenylbutanoic acid, L-O-methyltyrosine, and L-4-nitrophenylalanine have been synthesized. These analogues were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-l,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Two of the above analogues, Pro-Ahx-Gly-NH₂ (3) and Pro-Phe-Gly-NH₂ (6), showed significant activity in this assay system. Pro-Ahx-Gly-NH₂ produced a 16% enhancement of ADTN binding at 0.1 uM, while Pro-Phe-Gly-NH₂ enhanced the binding of ADTN by 31% at a concentration of 1uM.