Exploring the bioisosterism of proline residue in melanostatin neuropeptide using heteroaromatic scaffolds

Parkinson’s disease (PD) is the most common motor neurodegenerative disorder of the central nervous system, affecting 20 million people worldwide. Common symptoms include tremors, bradykinesia, gait alterations, sleeping disorders, fainting, and dementia. Currently, PD treatments are focused on dopamine (DA) potentiation through the administration of a DA precursor - levodopa (L-DOPA) - and coadministration of inhibitors of the catechol-O-methyl transferase and monoamine oxidase B enzymes. Even though L-DOPA regimen is able to control the progression of PD motor symptoms, long-term therapy causes serious health concerns. In this sense, pharmacological alternatives are mandatory.

Melanostatin (MIF-1), is an endogenous hypothalamic neuropeptide derived from the oxytocin hormone that acts as a positive allosteric modulator (PAM) of the D₂ Receptors (D₂R). By increasing the D₂R affinity for DA, these receptors are activated at lower DA concentration, being thus clinically relevant. Previous studies developed by our research group reveal that the replacement of L-Proline (Pro) residue by heteroaromatic scaffolds are well tolerated, rendering analogues with PAM activity comparable to the parent neuropeptide.

In this work, twelve novel MIF-1 analogues were synthesized and chemically characterized by incorporation of Niacin, as a Pro surrogate. Preliminary pharmacological functional assays demonstrated that these peptidomimetics enhanced the DA potency more than 2-fold at subnanomolar concentration (0.01 nM), showing a behaviour compatible with PAM at that concentration.

This work is expected to provide useful structure-activity relationship information for the rational design of novel MIF-1 peptidomimetics, paving the way for the development of new anti-Parkinson hits.