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Study · In vitro (cells) · 2025

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

Sampaio-Dias IE, Costa-Almeida HF, Correia XC, Silva-Reis SC, Costa VM, Brea J, Loza MI, Rodríguez-Borges JE, García-Mera X

ACS medicinal chemistry letters24 Jul 2025Cited by 4 (Europe PMC)

PMID40832547 (opens in a new tab)PMCIDPMC12358994 (opens in a new tab)DOI10.1021/acsmedchemlett.5c00287 (opens in a new tab)PepBankPUB-40832547
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Summary

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.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01LabIn vitro (cells)Activity measurement

    In receptor functional assays, MIF‑1 showed lower performance than compound 9 in modulation of dopamine potency.

    In plain wordsIn lab tests, MIF‑1 showed weaker dopamine potency modulation than compound 9.

    Peptide
    MIF-1 (Pro-Leu-Gly-NH2)
    Outcome
    DecreaseDopamine potency modulation
    Study

    n: not reported in source

    D2 receptor functional assay
    Comparator
    methyl l-pipecolyl-l-leucylglycinate (9)
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    22 Oct 2026, 02:26 UTC

    Study results updated

  2. Version 1

    21 Oct 2026, 18:59 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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