| Autor: |
Sampaio-Dias IE; LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal., Reis-Mendes A; UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal., Costa VM; UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal., García-Mera X; Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain., Brea J; Innopharma Screening Platform, Biofarma Research group, Centre of Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain., Loza MI; Innopharma Screening Platform, Biofarma Research group, Centre of Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain., Pires-Lima BL; LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal., Alcoholado C; Department of Cellular Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, Campus de Teatinos, 29071 Málaga, Spain., Algarra M; Department of Inorganic Chemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, 29071 Málaga, Spain., Rodríguez-Borges JE; LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal. |
| Abstrakt: |
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 (D 2 R), is being explored as a novel pharmacological approach focused on D 2 R 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 D 2 R. |
