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

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.