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Synthesis, Pharmacological, and Toxicological Evaluation of Potent Melanostatin Peptidomimetics Incorporating Chiral β-Amino Acids as Proline Surrogates
1 , * 1 , 1, 2 , 1 , 2, 3 , 2, 3 , 4 , 1
1  LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
2  UCIBIO/REQUIMTE - Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal.
3  Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Phamarcy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal.
4  Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Praza do Seminario de Estudos Galegos, 15705 Santiago de Compostela, Spain.
Academic Editor: Maria Emília Sousa (registering DOI)

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.

Keywords: β-Amino Acids; Melanostatin; Neuropeptides; Parkinson's Disease; Peptidomimetics