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Related Experiment Videos

Amide bond replacements incorporated into CCK-B selective "dipeptoids".

C I Fincham1, M Higginbottom, D R Hill

  • 1Parke-Davis Neuroscience Research Center, Addenbrookes Hospital Site, Cambridge, U.K.

Journal of Medicinal Chemistry
|April 17, 1992
PubMed
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Researchers explored replacing the amide bond in CCK-B receptor ligands with 11 alternatives. Some modifications improved binding affinity, while a thiazole replacement yielded CCK-A receptor selectivity.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Organic Synthesis

Background:

  • The cholecystokinin-B (CCK-B) receptor is a target for various therapeutic applications.
  • Dipeptoid ligands are crucial in modulating CCK-B receptor activity.
  • Understanding structure-activity relationships is key to designing potent and selective ligands.

Purpose of the Study:

  • To synthesize novel CCK-B receptor ligands by replacing the central amide bond.
  • To evaluate the binding affinities and selectivities of these modified ligands for CCK-A and CCK-B receptors.
  • To investigate the impact of different amide bioisosteres on ligand-receptor interactions.

Main Methods:

  • Chemical synthesis of 11 distinct amide bond replacements in CCK-B dipeptoid scaffolds.

Related Experiment Videos

  • Assessment of CCK-A and CCK-B receptor binding affinities using IC50 values.
  • Molecular modeling to quantify steric, lipophilic, and hydrogen bonding properties of replacements.

    • Main Results:

    • Most amide replacements resulted in weaker affinity and reduced selectivity for the CCK-B receptor compared to the parent compound.
    • Appending a fumarate side chain enhanced binding affinity for the CCK-B receptor (e.g., compound 36, CCK-B IC50 = 38.8 nM).
    • A 4,5-dihydro-1,3-thiazole replacement (compound 5) exhibited selectivity for the CCK-A receptor (CCK-A IC50 = 125 nM, CCK-B IC50 = 2580 nM).

    Conclusions:

    • Amide bond modifications significantly impact CCK receptor binding profiles.
    • Strategic design, such as incorporating fumarate or thiazole moieties, can optimize ligand affinity and selectivity.
    • The study provides valuable data for the rational design of future CCK receptor modulators.