Synthesis, Pharmacological, and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of DR.

This work describes the synthesis and pharmacological evaluation of picolinoyl-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) as dopamine modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated -propylapomorphine ([H]-NPA) at dopamine D receptors (DR). Methyl picolinoyl-l-valyl-l-alaninate (compound ) produced a statistically significant increase in the maximal [H]-NPA response at 0.01 nM (11.9 ± 3.7%), which is close to the effect of MIF-1 in this assay at same concentration (18.3 ± 9.1%). Functional assays measuring cAMP mobilization in the presence of dopamine corroborate the activity of peptidomimetic as a positive allosteric modulator (PAM) of DR. In this assay, produced a typical bell-shaped dose-response curve similar to that of the parent neuropeptide (18.3 ± 7.1% for vs 15.4 ± 5.5% for MIF-1, both at 0.1 nM). Dose-response curves for dopamine in the presence of show EC (0.33 ± 0.21 μM for vs 0.17 ± 0.07 μM for MIF-1) and (86.0 ± 5.4% for vs 93.6 ± 4.4% for MIF-1) comparable to those of MIF-1, both at 0.01 nM. Furthermore, peptidomimetic was tested for agonist activity at the human DR and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of DR. Cytotoxic and neurotoxic assays were performed for peptidomimetic using HEK 293T cells and cortex neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting this analogue displays no toxicity effect in these assays up to 100 μM. Conformational energy minimization for shows that this peptidomimetic cannot adopt the postulated type-II β-turn bioactive conformation, endorsing the possibility of an extended bioactive conformation as claimed by other researchers as a second bioactive conformation of MIF-1. Overall, the pharmacological and toxicological profile of peptidomimetic together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.