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Study · In vitro (cells) · 2026

2 results

Discovery of bridged melanostatin derivatives as potent allosteric modulators of the dopamine D2 receptors with improved permeability.

Sampaio-Dias IE, Costa-Almeida HF, Correia XC, Pires-Lima BL, Contino M, Perrone MG, Graziano G, Brea J, Loza MI, Sotelo E, Preto MAC, Leão PN and 5 more

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Reis-Mendes A, Costa VM, Maestro MA, Rodríguez-Borges JE, García-Mera X

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie12 Jun 2026

PMID42284887 (opens in a new tab)DOI10.1016/j.biopha.2026.119620 (opens in a new tab)PepBankPUB-42284887
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Summary

Melanostatin (MIF-1) is an endogenous positive allosteric modulator (PAM) of dopamine D2 receptors (D2R) with recognized therapeutic potential in central nervous system (CNS) disorders associated with dopaminergic dysfunction, particularly Parkinson's disease. However, the therapeutic development of MIF-1 has been limited by poor pharmacokinetic properties. Building on previous studies of conformationally constrained MIF-1 analogs, the present work describes the design, synthesis, and comprehensive functional, toxicological, and permeability evaluation of new bridged derivatives incorporating the enantiopure scaffold (1R,3S,4S)-2-azanorbornane-3-carboxylic acid as a hybrid prolyl/pipecolyl surrogate. The target MIF-1 derivatives were synthesized through a concise and stereoselective route, and their absolute configuration was unequivocally established by X-ray crystallography. Pharmacological assays at human D2R identified four active derivatives (7b, 8d, 9c, and 9d) that potentiated dopamine responses by 5.3- to 6.6-fold at concentrations as low as 10 pM, consistent with PAM-like activity. Toxicological profiling in HepG2 (100 µM) and differentiated SH-SY5Y neuronal cells (up to 200 µM) confirmed that these compounds are well tolerated at supra-pharmacological concentrations, except for 9c. Additionally, these compounds exhibited reduced P-gp-mediated efflux and improved Caco-2 permeability compared to MIF-1. Overall, these findings identify 2-azanorbornane as a promising scaffold for the development of D2R PAM ligands with favorable pharmacokinetic and safety profiles.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

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

  1. 01LabIn vitro (cells)Pharmacokinetics

    In cell assays, native MIF‑1 had greater P-gp-mediated efflux than the tested bridged derivatives.

    In plain wordsIn cells, native MIF‑1 had more transporter-mediated export than the tested modified peptides.

    Peptide
    MIF-1 (Pro-Leu-Gly-NH2)
    Outcome
    IncreaseP-gp-mediated efflux
    Study

    n: not reported in source

    Permeability and efflux assays
    Comparator
    Tested bridged MIF-1 derivatives
    Outcome group
    Pharmacokinetics · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Additionally, these compounds exhibited reduced P-gp-mediated efflux and improved Caco-2 permeability compared to MIF-1.
  2. 02LabIn vitro (cells)Pharmacokinetics

    In Caco-2 assays, native MIF‑1 had lower permeability than the tested bridged derivatives.

    In plain wordsIn cells, native MIF‑1 crossed the Caco-2 cell barrier less readily than the tested modified peptides.

    Peptide
    MIF-1 (Pro-Leu-Gly-NH2)
    Outcome
    DecreaseCaco-2 permeability
    Study

    n: not reported in source

    Caco-2 cells
    Comparator
    Tested bridged MIF-1 derivatives
    Outcome group
    Pharmacokinetics · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Additionally, these compounds exhibited reduced P-gp-mediated efflux and improved Caco-2 permeability compared to MIF-1.

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

Version history

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  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

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