An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2014 by T. Kenakin. A recording of the lecture is included as supporting information and can also be viewed online here: https://www.youtube.com/ watch?v=xrP81AQ8l-8. Pharmacological models used to describe drug agonism and antagonism have evolved over the past 20 years from a parsimonious model describing single active and inactive receptor states to models of multiconformational receptor systems modified by ligand conformational selection. These latter models describe the observed, presently underexploited, pharmacological mechanism of ligand-directed biased signalling. Biased signals can be quantified with transduction coefficients (ΔΔLog(τ/KA) values), a scale grounded in the Black/Leff operational model; this enables the optimization of biased profiles through medicinal chemistry. The past decades have also brought the availability of new technologies to measure multiple functional effects mediated by seven transmembrane receptors. These have confirmed that drugs can have many efficacies, which may be collaterally linked, that is there is no linear sequence of activities required. In addition, new functional screening assays have introduced increasing numbers of allosteric ligands into drug discovery. These molecules are permissive (they do not necessarily preclude endogenous signalling in vivo); therefore, they may allow better fine tuning of pathological physiology. The permissive quality of allosteric ligands can also change the quality of endogenous signalling efficacy ('induced bias') as well as the quantity of signal; in this regard, indices related to ΔΔLog(τ/KA) values (namely ΔLog(αβ) values) can be used to quantify these effects for optimization in the drug discovery process. All of these added scales of drug activity will, hopefully, allow better targeting of candidate molecules towards therapies.

Potency Ratio = \frac{{normalK}_{A 1} (1 + τ_{2})}{{normalK}_{A 2} (1 + τ_{1})}

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Section: Biased Agonistsmentioning

confidence: 99%

Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors

Kenakin

2015

“…The data set in Figure 2 (i.e. the individual control E /[A] curves and the associated individual E /[A] curves obtained in the presence of DCITC) were fitted globally to the operational model of agonism shown in (Black and Leff, 1983; Black et al. , 1985), by using either the single‐ or two‐curve method described in Methods .…”

Section: Resultsmentioning

confidence: 99%

“…The equilibrium dissociation constant ( K A ) of salbutamol, terbutaline, procaterol and formoterol in HASM was estimated by operational model fitting (Black and Leff, 1983; Black et al. , 1985) using one or two experimental approaches.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

An estimation of β₂‐adrenoceptor reserve on human bronchial smooth muscle for some sympathomimetic bronchodilators

Giembycz

2009

Background and purpose:The b2-Adrenoceptor on human pro-inflammatory cells is exquisitely sensitive to desensitization, whereas b2-adrenoceptor-mediated relaxation of human airways smooth muscle (HASM) is relatively resistant to this phenomenon. An explanation for this discrepancy is that a large b2-adrenoceptor 'reserve' exists on HASM cells for sympathomimetic bronchodilators, which protects against desensitization. Experimental approach: The operational model of agonism was used to estimate the affinity of salbutamol, terbutaline, formoterol and procaterol for the b2-adrenoceptors in methacholine (MCh)-contracted HASM from which the relationship between fractional receptor occupancy and relaxation was determined. This analysis was performed under conditions of fractional, irreversible, b2-adrenoceptor inactivation and, for salbutamol and terbutaline only, by the comparative method of Barlow et al. The affinity of salbutamol for the b2-adrenoceptor guinea-pig eosinophils and the receptor/occupancy-response relationship for the suppression of the respiratory burst (an index of pro-inflammatory cell function) was also determined. Key results: For salbutamol and terbutaline, both pharmacological approaches yielded in HASM discrepant affinity estimates (values differed, maximally, by 0.67 log10 unit). However, affinity values more closely agreed (difference <0.47 log10 unit), when operational analysis was performed on data corrected for 'fade' of the MCh-induced contraction. Plots of fractional b2-adrenoceptor occupancy versus relaxation indicated a receptor 'reserve' for all agonists tested at all levels of response. In contrast, minimal receptor reserve was detected for the ability of salbutamol to suppress respiratory burst activity in eosinophils. Conclusions and implications:These data may help explain the relative inability of sympathomimetic bronchodilators to render HASM tolerant to b2-adrenoceptor-mediated relaxation. (2009) British Journal of Pharmacology

“…

E = \frac{E_{m} τ^{n} {[A]}^{n}}{{(K_{a} + [A])}^{n} + τ^{n} {[A]}^{n}},

where E is the pharmacological effect, E m is the maximum effect of the system, [ A ] is the concentration of the agonist A , τ is the operational efficacy of A in the receptor system, K a is the dissociation constant of A for the receptor and n is a parameter related to the slope of the E /[ A ] curves. A value of n equal to 1 yields rectangular hyperbolic E /[ A ] curves, whereas values of n greater or less than 1 allow for steeper or flatter curves than the rectangular hyperbola, respectively (Black and Leff, ; Black et al ., ).…”

Section: Introductionmentioning

confidence: 97%

A method for the quantification of biased signalling at constitutively active receptors

Hall

Giraldo

2018