Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder of central nervous system (CNS), characterized by the progressive loss of mesencephalic dopaminergic neurons. Current therapies provide symptomatic relief but do not halt disease progression, highlighting the urgent need for novel and innovative therapeutic strategies.

Melanostatin (MIF-1), a hypothalamic neuropeptide and positive allosteric modulator (PAM) of dopamine D2 receptors, has emerged a promising candidate for PD treatment. However, its peptide nature restricts clinical use due to its poor oral bioavailability and limited metabolic stability.

In this work, we designed and synthesized twelve novel analogs using pyridine-based carboxylic acids as prolyl surrogates to address the pharmacokinetic limitations of MIF-1. Pyridine-based scaffolds are known for their structural versatility and CNS drug-like properties, including neuroprotective and neurotransmitter-modulating effects.

Structure-cytotoxicity relationship studies in differentiated SH-SY5Y cells identified that, in this group of analogs, the methyl ester group acts as a toxicophore, whereas the corresponding amide counterparts exhibited improved toxicological profiles. These findings offer valuable insights for the development of novel pyridine-based MIF-1 analogs with adequate toxicological profiles.

The analogs identified in this preliminary study are suitable to undergo pharmacological functional assays to characterize PAM activity, contributing to the development of safer and more effective anti-Parkinson agents.