Dual-Acting Vitamin B3-Melanostatin Neuropeptide Hybrids as Potent Modulators of the Dopamine D2 Receptors with Neuroprotective Activity

  • J Med Chem. 2026 Jul 9;69(13):15597-15613. doi: 10.1021/acs.jmedchem.6c00697.
Beatriz L Pires-Lima  1  2 ,  Sara C Silva-Reis  1  3 ,  Xavier Cruz Correia  1 ,  Hugo F Costa-Almeida  1 ,  Vera M Costa  3  4 ,  Xerardo García-Mera  5 ,  José Brea  6 ,  María I Loza  6 ,  Marialessandra Contino  7 ,  Maria Grazia Perrone  7 ,  Giovanni Graziano  7 ,  Nuno Vale  2  8  9 ,  José E Rodríguez-Borges  1 ,  Ivo E Sampaio-Dias  1
Affiliations
  • 1. LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto 4169-007, Portugal.
  • 2. PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal.
  • 3. UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto 4050-313, Portugal.
  • 4. Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto 4050-313, Portugal.
  • 5. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela E-15782, Spain.
  • 6. Innopharma Screening Platform. Biofarma Research Group. Centre of Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela E-15782, Spain.
  • 7. Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, Bari 70125, Italy.
  • 8. RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Porto 4200-450, Portugal.
  • 9. Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Porto 4200-450, Portugal.
PMID: 42312436 DOI: 10.1021/acs.jmedchem.6c00697
Abstract

Parkinson's disease (PD) therapy remains limited by complications of the levodopa regimen, highlighting the need for novel therapeutic strategies to modulate dopaminergic signaling. Melanostatin (MIF-1) has attracted attention as a privileged scaffold for dopamine D2 receptor (D2R) modulation due to its intrinsic positive allosteric modulatory activity, although improved potency and drug-like properties are required for translation. In this work, nicotinic acid (Nic), a vitamer of vitamin B3, was employed as a proline (Pro) bioisostere, generating 12 vitamin B3-MIF-1 hybrids. Nicotinoyl-l-leucylglycinamide (6c) emerged as a lead compound, promoting a 5.11-fold enhancement of dopamine potency at 0.01 nM and displaying neuroprotective activity at 50-100 μM in dopaminergic-differentiated SH-SY5Y cells. Additionally, Pro-to-Nic substitution showed no cytotoxicity in HepG2, reduced P-glycoprotein-mediated efflux, and preserved β-turn conformational propensity, supporting improved oral drug-like properties. Collectively, these findings identify 6c as a dual-acting lead and establish Nic as a privileged Pro surrogate for next-generation MIF-1-based PD therapeutics.

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