Discovery of New Potent Positive Allosteric Modulators of Dopamine D Receptors: Insights into the Bioisosteric Replacement of Proline to 3-Furoic Acid in the Melanostatin Neuropeptide.

The control of Parkinson's disease (PD) is challenged by the motor and non-motor fluctuations as well as dyskinesias associated with levodopa long-term therapy. As such, pharmacological alternatives to reduce the reliance on this drug are needed. Melanostatin (MIF-1), a positive allosteric modulator (PAM) of D receptors (DR), is being explored as a novel pharmacological approach focused on DR potentiation. In this work, 3-furoic acid () was successfully employed as an l-proline (Pro) surrogate, affording two potent MIF-1 analogues, methyl 3-furoyl-l-leucylglycinate () and 3-furoyl-l-leucylglycinamide (). In this series, the C-terminal carboxamide moiety was found crucial to enhancing the potency and toxicological profile, yet it is not considered a requisite for the PAM activity. Conformational analysis excludes from adopting the claimed type II β-turn. The discovery and validation of as a lead compound open a new avenue for the development of a novel class of anti-Parkinson therapeutics targeting the DR.