This project describes the synthesis, pharmacological and biological evaluation of new classes of mimetic compounds for neuropeptide MIF-1 (L-prolyl-L-leucylglycinamide), which perform important roles in central nervous system. The main objective was study the replacement of L-proline by heteroaromatic system such as picolinic acid. A new series of eight pyridine-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) were obtained and tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at dopamine D₂ receptors (D₂R).

Methyl picolinoyl-L-valyl-L-alaninate (compound 6b) increased significantly the maximal [3H]-NPA response at 0.01 nM (11.9 ± 3.7 %), which is close to the effect of MIF-1 at same concentration (18.3 ± 9.1 %). In this assay, a typical bell-shaped dose–response curves for dopamine shows values of EC₅₀ of 0.33 ± 0.21 μM and 0.17 ± 0.07 μM and E_max of 86.0 ± 5.4 % and 93.6 ± 4.4 %, for 6b and MIF-1 respectively, both at 0.01 nM. Furthermore, 6b was tested for agonist activity at the human D₂R and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of D₂R. Cytotoxic and neurotoxic assays were performed for peptidomimetic 6b and the results suggest this analogue displays no toxicity effect in these assays up to 100 μM.

Overall, the pharmacological and toxicological profile of peptidomimetic 6b together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.