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

• Synthesis of 11 novel analogs of l-prolyl-l-leucylglycinamide (PLG).
• The prolyl residue of PLG was replaced by a 3,5-disubstituted proline scaffold.
• These analogs were tested as allosteric modulators of dopamine D2 receptors.
• Compounds 18b and 19b increased [3H] NPA binding at concentrations of 10−12–10−9 M.

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 [3H]-N-propylnorapomorphine to short isoform of human dopamine D2 receptors.Compounds 18b and 19b, increased [3H] 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.

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