Synthesis, Pharmacological, and Toxicological Evaluation of Potent Melanostatin Peptidomimetics Incorporating Chiral β-Amino Acids as Proline Surrogates

Melanostatin (MIF-1, Fig. 1) is an endogenous tripeptide (Pro-Leu-Gly-NH₂) with several functions within the central nervous system (CNS). It has been widely recognized as a potent and selective positive allosteric modulator (PAM) of the dopamine D₂ receptors (D₂R),[1] with potential biomedical applications in neurological diseases such as Parkinson’s disease (PD). Upon binding to their allosteric binding sites, PAM induce conformational changes that increase binding affinity of orthosteric ligands to the receptor. Comparatively to orthosteric drugs, PAM present several advantages such as high specificity and reduced side effects since they are only effective in the presence of the orthosteric ligand.[2]

Despite its undeniable pharmacological potential in PD, MIF-1 exhibits reduced stability towards CNS-derived peptidases and low gastrointestinal bioavailability,[3,4] hampering oral administration. In this work, the bioisosteric replacement of prolyl residue with non-proteinogenic amino acids is disclosed as a strategy to overcome the unfavorable pharmacokinetic profile of MIF-1 without compromising its PAM activity.

Six novel MIF-1 proline mimetics (Fig. 1) bearing cyclic β-amino acids were designed, synthesized and pharmacologically evaluated. In functional assays at D₂R, one of these peptidomimetics exhibits a superior performance (lower EC₅₀) than MIF-1 at 1 nM. Furthermore, no cytotoxic effect was observed for this compound at 100 µM using differentiated human neuronal SH-SY5Y cells. Further studies are currently underway to determine its chemical stability and in vitro biological permeability. The discovery of a new potent PAM of the D₂R with a safe cytotoxic profile opens new directions for the development of complementary anti-Parkinson therapies.