Discovery Of New Potent Positive Allosteric Modulators Of Dopamine D-2 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-2 receptors (D2R), is being explored as a novel pharmacological approach focused on D2R potentiation. In this work, 3-furoic acid (3-Fu) was successfully employed as an L-proline (Pro) surrogate, affording two potent MIF-1 analogues, methyl 3-furoyl-L-leucylglycinate (4a) and 3-furoyl-L-leucylglycinamide (6a). 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 4a from adopting the claimed type II beta-turn. The discovery and validation of 6a as a lead compound open a new avenue for the development of a novel class of anti-Parkinson therapeutics targeting the D2R.