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Related Experiment Videos

Structure function differences in nonpeptide CCR1 antagonists for human and mouse CCR1.

James Onuffer1, Margaret A McCarrick, Laura Dunning

  • 1Department of Immunology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94806, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|February 8, 2003
PubMed
Summary

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Novel 4-hydroxypiperidine antagonists show significant potency differences between human and mouse chemokine receptor CCR1. Structural modifications, like linker length, can achieve equipotency across species, aiding ligand binding domain identification.

Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets.
  • Identifying ligand binding domains is key for drug discovery.
  • Species-specific antagonist potencies offer insights into receptor-ligand interactions.

Purpose of the Study:

  • To investigate structure-activity relationships of novel 4-hydroxypiperidine antagonists for human and mouse CCR1.
  • To utilize species differences in antagonist potency to identify CCR1 ligand binding domains.
  • To present a model for antagonist interaction with human CCR1.

Main Methods:

  • High-throughput screening to discover initial antagonists.
  • Optimization of lead compounds.

Related Experiment Videos

  • Receptor binding and functional assays to determine antagonist potency.
  • Structure-activity relationship analysis across human and mouse CCR1.

    • Main Results:

    • Novel 4-hydroxypiperidine antagonists were identified and optimized.
    • Significant potency differences were observed for antagonists between human and mouse CCR1.
    • A specific analog (BX 511) with a modified linker achieved equipotency for both species.
    • Structure-activity relationships revealed key determinants of species-specific potency.

    Conclusions:

    • Species differences in antagonist potency are a valuable tool for mapping GPCR ligand binding sites.
    • 4-hydroxypiperidine antagonists provide a versatile series for studying CCR1.
    • Structural modifications can modulate antagonist activity across species, informing drug design for CCR1.