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

Melanostatin (MIF-1) is a naturally occurring neuropeptide acting as a positive allosteric modulator (PAM) of dopamine D receptors (DR), 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 DR. In this series, methyl l-pipecolyl-l-leucylglycinate () 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. conformational studies demonstrate that 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.