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Potential errors in agonist dissociation constant estimation caused by desensitization.

P Leff

    Journal of Theoretical Biology
    |July 21, 1986
    PubMed
    Summary
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    Receptor desensitization can lead to inaccurate drug measurements, potentially overestimating agonist dissociation constants. This model predicts errors in drug quantification, even when desensitization is not obvious.

    Area of Science:

    • Pharmacology
    • Computational Biology
    • Biophysics

    Background:

    • Receptor desensitization is a crucial phenomenon affecting drug response.
    • Existing models may not fully capture acute receptor loss impacts on drug quantification.
    • The operational model of agonism (OMA) provides a framework for analyzing agonist-receptor interactions.

    Purpose of the Study:

    • To develop and analyze a simple model of receptor desensitization.
    • To predict the consequences of acute receptor loss on pharmacological quantification of agonist action.
    • To assess the impact of desensitization on agonist concentration-effect curves and parameter estimation.

    Main Methods:

    • Incorporation of the Katz desensitization scheme into the Black & Leff operational model of agonism.

    Related Experiment Videos

  • Simulation of pharmacological effect-time profiles.
  • Analysis of agonist concentration-effect curves and estimated parameters.

    • Main Results:

    • Simulated effect-time profiles illustrate the detectability of 'fade' and deviations from equilibrium conditions.
    • Agonist concentration-effect curves can be rightwardly displaced due to desensitization.
    • Estimates of agonist dissociation constants may be overestimated, irrespective of fade detectability.
    • Agonist efficacy estimates remain unaffected by desensitization.

    Conclusions:

    • Receptor desensitization can introduce significant errors in pharmacological measurements.
    • Overestimation of agonist dissociation constants can impact receptor classification and drug development.
    • The developed model provides insights into the quantitative consequences of desensitization in drug action.