Mechanistic analysis of the function of agonists and allosteric modulators: Reconciling two-state and operational models

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Abstract

Two-state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor-dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two-state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one-by-one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism. © 2013 The British Pharmacological Society.
Original languageEnglish
Pages (from-to)1189-1202
JournalBritish Journal of Pharmacology
Volume169
Issue number6
DOIs
Publication statusPublished - 1 Jul 2013

Keywords

  • agonist efficacy
  • G protein-coupled receptors
  • mathematical modelling
  • model fitting
  • negative allosteric modulators
  • operational model of agonism
  • operational model of allosterism
  • parameter estimation
  • positive allosteric modulators
  • two-state receptor model

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