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Related Experiment Videos

Bivalent biogenic amine reuptake inhibitors.

Keith Fandrick1, Xianqi Feng, Aaron Janowsky

  • 1Human BioMolecular Research Institute, 5310 Eastgate Mall, 92121, San Diego, CA, USA.

Bioorganic & Medicinal Chemistry Letters
|June 12, 2003
PubMed
Summary

Researchers developed novel aryltropane-based bivalent ligands to study transporter inhibition. Ligand 4 demonstrated high potency for the human dopamine transporter, offering potential for targeted therapeutic development.

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Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs.

ACS pharmacology & translational science·2026

Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Pharmacology

Background:

  • Monoamine transporters, including dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters, are crucial targets for neurological and psychiatric disorders.
  • Bivalent ligands, which possess two pharmacophores linked by a spacer, offer unique opportunities for modulating transporter activity with enhanced selectivity.

Purpose of the Study:

  • To synthesize and characterize a series of novel aryltropane-based bivalent ligands.
  • To evaluate the binding affinity and reuptake inhibition potency of these ligands at human DAT, SERT, and NET.
  • To assess the selectivity of the most potent compounds for specific monoamine transporters.

Main Methods:

  • Chemical synthesis of aryltropane derivatives with varying linker lengths and structures.

Related Experiment Videos

  • In vitro binding assays to determine ligand affinity (Ki) for human DAT, SERT, and NET.
  • Neurotransmitter reuptake inhibition assays to measure functional potency (IC50).

    • Main Results:

    • A series of bivalent ligands based on the aryltropane scaffold were successfully synthesized.
    • The bivalent ligand 4, featuring an octamethylene spacer, exhibited high binding potency and reuptake inhibition efficacy for the human dopamine transporter.
    • Ligand 4 demonstrated significant selectivity for DAT over SERT and NET, with a discrimination ratio of 130 for DAT.

    Conclusions:

    • Aryltropane-based bivalent ligands represent a promising class of compounds for targeting monoamine transporters.
    • Ligand 4 shows potential as a selective inhibitor of the human dopamine transporter, warranting further investigation for therapeutic applications.
    • The design strategy utilizing bivalent ligands with specific linkers can achieve high transporter selectivity.