Dual-Acting Vitamin B <sub>3</sub> -Melanostatin Neuropeptide Hybrids as Potent Modulators of the Dopamine D <sub>2</sub> Receptors with Neuroprotective Activity
High Resolution Image Download MS PowerPoint Slide 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 D 2 receptor (D 2 R) 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 B 3, was employed as a proline (Pro) bioisostere, generating 12 vitamin B 3 -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.
Authors
- Xerardo Garcı́a-Mera (ORCID: https://orcid.org/0000-0001-5218-6351)
- Ivo E. Sampaio‐Dias (ORCID: https://orcid.org/0000-0002-9071-6197)
- Maria Grazia Perrone (ORCID: https://orcid.org/0000-0003-4195-5228)
- Beatriz L. Pires-Lima (ORCID: https://orcid.org/0000-0003-1464-7254)
- Hugo F. Costa-Almeida (ORCID: https://orcid.org/0000-0002-9034-2076)
- Nuno Vale (ORCID: https://orcid.org/0000-0002-1283-1042)
- Jose Manuel Brea (ORCID: https://orcid.org/0000-0002-5523-1979)
- Giovanni Graziano (ORCID: https://orcid.org/0000-0002-5575-3240)
- Xavier Cruz Correia (ORCID: https://orcid.org/0000-0002-1440-9873)
- Marı́a Isabel Loza (ORCID: https://orcid.org/0000-0003-4730-0863)
- José E. Rodríguez‐Borges (ORCID: https://orcid.org/0000-0002-9104-1670)
- Vera Marisa Costa (ORCID: https://orcid.org/0000-0002-0471-2756)
- Sara C. Silva-Reis (ORCID: https://orcid.org/0000-0003-2024-0696)
- Marialessandra Contino (ORCID: https://orcid.org/0000-0002-0713-3151)
Institutions
- Universidade do Porto (PT)
- Universidade de Santiago de Compostela (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Healthwise (US)
- Decision Sciences (United States) (US)
- Institute of Organic Chemistry (HU)
- Rede de Química e Tecnologia (PT)
- Norwegian Institute of Bioeconomy Research (NO)
- University of Bari Aldo Moro (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-06-18
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00697
- Primary Topic
- Macrophage Migration Inhibitory Factor
- Type
- article
- Field-Weighted Citation Impact
- 0.00