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

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.