AN OPERATIONAL MODEL OF PHARMACOLOGICAL AGONISM - THE EFFECT OF E/[A] CURVE SHAPE ON AGONIST DISSOCIATION-CONSTANT ESTIMATION
AN OPERATIONAL MODEL OF PHARMACOLOGICAL AGONISM - THE EFFECT OF E/[A] CURVE SHAPE ON AGONIST DISSOCIATION-CONSTANT ESTIMATION
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DOI：
10.1111/j.1476-5381.1985.tb12941.x
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发表时间：
1985-01-01
影响因子：
7.3
通讯作者：
WOOD, J
中科院分区：
文献类型：
--
作者：
BLACK, JW;LEFF, P;WOOD, J
分析了药理激动剂的操作模型，以预测矩形双曲线和非双曲线激动剂的行为-浓度效应E/[A]随受体浓度[Ro]的变化。在非双曲线情况下，不可逆拮抗可导致E/[A]曲线梯度变化，但在双曲线情况下不会；在这两种情况下，对激动剂解离常数(Ka)的估计在理论上是有效的。5-羟色胺(5-HT)收缩兔离体主动脉可产生陡峭的E/[A]曲线。苯氧基苯甲胺(PBZ)的不可逆拮抗作用使E[A]曲线变平，与理论预测一致。用5-HTE/[A]曲线对5-HTE/[A]曲线进行拟合，得到了5-HTE/[A]的估计值，与用Furchgot‘’S零值法得到的估计值没有显著差异。激动性操作模型似乎定性和定量地考虑了[Ro]变化对双曲线和非双曲线E/[A]曲线的影响。在不可逆拮抗作用可以用来估计Ka的条件下，直接将操作模型与E/[A]数据拟合是一种有效、经济和分析简单的替代传统零值法的方法。
An operational model of pharmacological agonism was analyzed to predict the behavior of rectangular hyperbolic and nonhyperbolic agonist-concentration effect, E/[A], curves with variation in receptor concentration, [Ro]. Irreversible antagonism is predicted to cause E/[A] curve gradient changes in nonhyperbolic cases but not in hyperbolic cases; in both cases estimation of agonist dissociation constants (KA) is theoretically valid. 5-Hydroxytryptamine (5-HT) produced steep E/[A] curves in contracting the rabbit isolated aorta preparation. Irreversible antagonism by phenoxybenzamine (Pbz) produced a flattened E[A] curve, consistent with theoretical predictions. Fitting 5-HT E/[A] curves in the presence and absence of Pbz to the model provided an estimate of KA for 5-HT which was not significantly different from the estimate obtained using Furchgott''s null method. The operational model of agonism appears to account qualitatively and quantitatively for the effects of [Ro] changes on hyperbolic and nonhyperbolic E/[A] curves. Under conditions where irreversible antagonism may be used to estimate KA, fitting the operational model directly to E/[A] data represents a valid, economical and analytically simple alternative to the conventional null method.