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Development of CCK-B antagonists.

D C Horwell1

  • 1Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, UK.

Neuropeptides
|July 1, 1991
PubMed
Summary
This summary is machine-generated.

Researchers developed novel non-peptide cholecystokinin (CCK) analogues, called dipeptoids, that act as CCK-B antagonists. One compound, PD134308, shows high affinity, selectivity, and potent anxiolytic effects in animal models.

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Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Pharmacology

Background:

  • Neuropeptide cholecystokinin (CCK) plays a role in various physiological processes.
  • CCK receptors, specifically CCK-A and CCK-B subtypes, are targets for therapeutic intervention.
  • Developing small molecule non-peptide analogues of neuropeptides presents a challenge in drug discovery.

Purpose of the Study:

  • To design and discover novel non-peptide analogues of cholecystokinin (CCK) with antagonist properties at the CCK-B receptor.
  • To identify a lead compound with high affinity, selectivity, and favorable pharmacokinetic properties for potential anxiolytic applications.

Main Methods:

  • Rational drug design based on the CCK 26-33 sequence.
  • Systematic chemical modification of a key dipeptide fragment (Boc-Trp-Phe-NH2) at N- and C-termini.

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  • In vitro binding assays to determine receptor affinity and selectivity.
  • In vivo pharmacological studies in anxiogenic animal models to assess anxiolytic efficacy via subcutaneous and oral administration.

    • Main Results:

    • Discovery of 'dipeptoids', a series of CCK-B antagonists.
    • Identification of PD134308 as a representative compound with high affinity (Ki = 1.7 nM) and selectivity (CCK-A/B ratio = 2500:1) for the CCK-B receptor.
    • PD134308 demonstrated robust, dose-dependent anxiolytic properties in multiple models following both subcutaneous and oral administration.
    • Chemical modifications enhanced stability against degradation and improved lipophilicity for blood-brain barrier penetration.

    Conclusions:

    • The developed dipeptoids represent a promising class of small molecule non-peptide CCK-B antagonists.
    • PD134308 exhibits significant potential as an anxiolytic agent due to its pharmacological profile.
    • The rational design strategy effectively translated peptide-based activity into a non-peptide small molecule with improved drug-like properties.