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Discovery of New Potent Positive Allosteric Modulators of Dopamine D2 Receptors: Insights into the Bioisosteric Replacement of Proline to 3‑Furoic Acid in the Melanostatin Neuropeptide

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journal contribution
posted on 16.04.2021, 20:10 by Ivo E. Sampaio-Dias, Ana Reis-Mendes, Vera Marisa Costa, Xerardo García-Mera, José Brea, María Isabel Loza, Beatriz L. Pires-Lima, Cristina Alcoholado, Manuel Algarra, José E. Rodríguez-Borges
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 D2 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 β-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.