Synthesis and pharmacological evaluation of melanostatin analogues containing Chiral β-amino acids as proline surrogates

Parkinson’s disease is the second most common neurodegenerative disease of the central nervous system, affecting millions of people worldwide and causing hundreds of thousands of deaths every year.

At the time, the therapeutic approach focuses on enhancing dopamine (DA) levels through the administration of levodopa (L-DOPA) and inhibitors of the catechol-O-methyl transferase and monoamine oxidase B enzymes. Despite the undeniable success of the L-DOPA therapy in reducing motor symptoms, PD remains a challenging neurological condition to manage due to motor fluctuations and dyskinesias associated with long-term therapy. In this regard, a pharmacological alternative to reduce the amount of L-DOPA required to manage the motor symptoms is, therefore, a health priority.

Melanostatin (MIF-1) is a neuropeptide derived from the oxytocin hormone and it acts as a positive allosteric modulator (PAM) of the DA receptor D₂ (D₂R), exhibiting anti-Parkinson activity. This neuropeptide is being explored to target the D₂R by increasing its affinity towards DA, requiring lower concentrations of this neurotransmitter to activate D₂R, being thus clinically relevant.

In this work, eight MIF-1 peptidomimetics bearing two different chiral β-amino acids as proline (Pro) surrogates were synthesized and chemically characterized. In vitro functional assays on cloned D₂R showed that these analogues display promising PAM activity. Among this series, two peptidomimetics exhibit higher potency than MIF-1, paving the way for the discovery of new hit peptidomimetics with anti-Parkinson activity.