Continuous variation of agonist affinity constants

Mackay, D.

doi:10.1016/0165-6147(88)90026-0

Cited by 30 publications

(16 citation statements)

References 2 publications

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“…In the case of the receptor isomerisation mechanism it has been shown that it is theoretically impossible, by use of traditional pharmacological methods (Stephenson, 1956;Furchgott, 1966;Barlow et al, 1967), to estimate agonist affinity independently of efficacy, with the consequence that affinity itself is overestimated (Colquhoun, 1987). The same predictions are made in the case of the ternary complex mechanism when the concentration of agonist-receptor complexes is similar to or less than the concentration of transducer units with which they interact (Mackay, 1988;Leff & Harper, 1989). However, it is predicted for both mechanisms that the magnitude of overestimation of affinity will be larger in the case of full agonist analysis by the receptor inactivation method of Furchgott (1966) than in the case of partial agonist analysis by either the interaction method (Stephenson, 1956) or the comparative method (Barlow et al, 1967).…”

Section: Introductionmentioning

confidence: 64%

“…In a number of recent articles (Colquhoun, 1987;Mackay, 1988;Kenakin, 1989;Leff & Harper, 1989) attention has been drawn to the theoretical unreliability of agonist affinity estimates obtained by pharmacological methods due to the operation of receptor isomerisation (del Castillo & Katz, 1957) and ternary complex (De Lean et al, 1978) mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological estimation of agonist affinity: detection of errors that may be caused by the operation of receptor isomerisation or ternary complex mechanisms

Leff¹,

Harper²,

Dainty³

et al. 1990

British J Pharmacology

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1 Recent theoretical studies have questioned the pharmacological estimation of agonist affinity. They showed that when receptor isomerisation or ternary complex mechanisms operate, the receptor inactivation method can substantially overestimate affinity, whereas methods for partial agonist analysis are more accurate. We previously suggested that the operation of such mechanisms and therefore the presence of errors could be detected by analysing the same partial agonist by the receptor inactivation and comparative methods. This paper describes the practical application of this test. 2 The ternary complex mechanism was simulated for a partial agonist under various conditions relating receptor (R) and transducer (T) concentrations, one of which also corresponds to the receptor isomerisation mechanism. The theoretical data so generated were then analysed by the inactivation-and comparative methods to quantify the magnitude of error of affinity estimation that could occur. 3 This analysis showed that for a partial agonist with approximately 85% of the activity of a full agonist, the inactivation method could produce an affinity (pKA) estimate up to 0.7 log1o units higher than that produced by the comparative method. This difference would occur when the total receptor concentration ([RO]) is less than or equal to the total transducer concentration ([To]). It also showed that the overestimation of affinity by the inactivation method was accompanied by drastic overestimation of Em, the maximal effect parameter. 4 The test was then exemplified using the muscarinic receptor system in the guinea-pig isolated left atrial preparation, where there is evidence that a ternary complex mechanism operates. The test agonist was pilocarpine, which produced on average 83% of the activity of the full agonist, carbachol. Pilocarpine was analysed in comparison with carbachol and by receptor inactivation in the same tissue resulting in small and statistically insignificant differences in Em (96.7% and 97.3% respectively) and pKA (5.03 and 4.95 respectively). 5 In conclusion, in this experimental system, there was no evidence for the errors in agonist affinity estimation predicted by theory. Although this conclusion only applies to this system and application of the test to others is necessary to establish the generality of the present results, further examination of the theoretical basis for the predicted errors is required.

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Section: Introductionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Pharmacological estimation of agonist affinity: detection of errors that may be caused by the operation of receptor isomerisation or ternary complex mechanisms

Leff¹,

Harper²,

Dainty³

et al. 1990

British J Pharmacology

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“…Mackay [30] proposed that the variation in affinity could be explained by a ternarycomplex model. This model assumes that the agonist-receptor complex interacts with a third component within the cell.…”

Section: Local Regulation Of Receptor Affinity By G Proteins and Othementioning

confidence: 99%

Variable Receptor Affinity and Tissue Sensitivity

Oriowo

Bevan²,

Bevan³

1991

J Vasc Res

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Vascular smooth muscle sensitivity to norepinephrine (NE), measured by contractile responses in vitro, varied in different arteries of the rabbit and also in the same vessels in other species. There was a good correlation between variation in the affinity of NE for the α₁-adrenoceptor and tissue sensitivity. The variation was continuous and probably not indicative of different receptor subtypes. Solubilization of α₁-adrenoceptors from the membrane changed the affinity for specific ligands while reconstitution restored it. Taken together, these results suggest the presence of a factor(s) within the receptor microenvironment capable of modulating affinity and hence tissue sensitivity to NE. In some blood vessels, receptor number was correlated significantly with affinity of the α₁-adrenoceptor for NE also. In general, the contribution of receptor number was considerably less than the affinity for NE.

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“…In the case of a-adrenoceptors (De Lean et al, 1978), dopamine (Wregget and De Lean, 1984) and muscarinic (Freedman et al, 1988) receptors it has been proposed that a ternary complex mechanism applies in which the activated state of the receptor is an agonist-receptor-G-protein complex. Recently, it has been shown (Mackay, 1988) that the operation of a ternary complex mechanism may lead to errors in agonist analysis by pharmacological methods. Specifically, when the concentration of G-proteins (denoted here as [Go]) is in excess of the concentration of receptors (denoted here as [Ro]), the receptor inactivation method is predicted to produce overestimates of agonist affinity (Mackay, 1988 in the absolute estimation of affinity and efficacy, the orders of affinity and efficacy determined by the comparative method will generally be correct; this is unlike the situation for the inactivation method where a high propensity for reversals in affinity order exists; (iv) in general, when the ternary complex mechanism operates the comparative method for partial agonist analysis produces more reliable information for the purposes of receptor classification than does the receptor inactivation method.…”

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confidence: 99%

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1989

British J Pharmacology

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Continuous variation of agonist affinity constants

Cited by 30 publications

References 2 publications

Pharmacological estimation of agonist affinity: detection of errors that may be caused by the operation of receptor isomerisation or ternary complex mechanisms

Pharmacological estimation of agonist affinity: detection of errors that may be caused by the operation of receptor isomerisation or ternary complex mechanisms

Variable Receptor Affinity and Tissue Sensitivity

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