Novel l-prolyl-l-leucylglycinamide (PLG) tripeptidomimetics based on a 2-azanorbornane scaffold as positive allosteric modulators of the D2R.

An efficient and straightforward orthogonal methodology was successfully developed to achieve constrained l-prolyl-l-leucylglycinamide (PLG) analogues starting from two proline mimetics based on a 2-azanorbornane scaffold. A preliminary dopamine D2 receptor radiolabeled binding assay with [3H]-N-propylnorapomorphine shows that enantiopurity of PLG peptidomimetics based on 2-azanorbornane is a requirement to achieve statistically significant positive modulators of the D2 receptor. This is the first documented active peptidomimetic of PLG whose bioactivity is not correlated with the C-terminal carboxamide pharmacophore and which cannot adopt the hypothesized type II β-turn conformation.