Proline Homologation in Melanostatin Neuropeptide: Discovery of Potent Modulators of the Dopamine D2 Receptors

ACS Med Chem Lett. 2025 Jul 24;16(8):1437-1444. doi: 10.1021/acsmedchemlett.5c00287. eCollection 2025 Aug 14.

ABSTRACT

Melanostatin (MIF-1) is a naturally occurring neuropeptide acting as a positive allosteric modulator (PAM) of dopamine D₂ receptors (D₂R), underscoring its potential for therapeutic use in central nervous system disorders associated with dopaminergic dysregulation, including depression, drug addiction, restless legs syndrome, tardive dyskinesia, and Parkinson’s disease. In this work, a new series of MIF-1 analogs using l-pipecolic acid as an l-proline surrogate was synthesized and pharmacologically evaluated by functional assays at the D₂R. In this series, methyl l-pipecolyl-l-leucylglycinate (9) was found to exhibit superior performance compared to MIF-1 by promoting a 4.1- and 4.2-fold increase of dopamine potency at 0.01 and 1 nM, respectively. In silico conformational studies demonstrate that 9 preferentially adopts a γ-turn, corroborating that neither the C-terminal carboxamide nor the postulated type II β-turn conformation is required for PAM activity. Toxicological assays in human dopaminergic SH-SY5Y neuronal cells show that this compound exhibits no significant toxicity up to 100 μM in the MTT reduction and neutral red uptake assays.

PMID:40832547 | PMC:PMC12358994 | DOI:10.1021/acsmedchemlett.5c00287