Synthesis and allosteric modulation of the dopamine receptor by peptide analogs of L-prolyl-L-leucyl-glycinamide (PLG) modified in the L-proline or L-proline and L-leucine scaffolds.

Novel analogs of L-prolyl-L-leucylglycinamide (PLG) were synthesized wherein the prolyl residue was replaced with other amino acids based on a 3,5-disubstituted proline scaffold. In some examples, the L-leucyl residue was also replaced by L-valine. These analogs were tested for their ability to enhance the binding of [(3)H]-N-propylnorapomorphine to short isoform of human dopamine D₂ receptors. Compounds 18b and 19b, increased [(3)H] NPA binding at concentrations between 10(-12) and 10(-9) M, which is similar to the effect of PLG in this assay and, provides evidences that these compounds are acting as allosteric modulators of dopamine D₂ receptors.