Dual-Acting Vitamin B<sub>3</sub>-Melanostatin Neuropeptide Hybrids as Potent Modulators of the Dopamine D<sub>2</sub> Receptors with Neuroprotective Activity.

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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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