Kenakin T P
Department of Cellular Biochemistry, Glaxo Inc. Research Institute, Glaxo Inc., Research Triangle Park, North Carolina 27709.
Mol Pharmacol. 1992 Apr;41(4):699-707.
A model is described that predicts the behavior of competitive antagonists in tissues with more than one receptor mediating response. The receptor stimuli for two receptor types are summed and processed, via a cellular stimulus-response mechanism, into tissue response. The primary receptor is described by a standard Langmurian isotherm, and a secondary receptor input with a variable maximal strength, for which the agonist has variable sensitivity, is added. The prediction of drug effects in this system does not depend on the way in which the two stimuli are combined or on the absolute magnitudes of the parameters used to make the calculations. The model is maximally flexible, in that no pharmacological significance is put on the magnitudes of the inputs from the secondary receptor system (i.e., they can vary with either agonist intrinsic efficacy, receptor number, or efficiency of stimulus-response coupling). The theoretical Schild regressions for selective antagonists in two-receptor systems are calculated for various secondary receptor inputs. These regressions generally are curvilinear whenever the secondary receptor significantly contributes to agonist response. These calculated data also indicate that minor variations in biological input from secondary receptor systems would obscure curvature in the Schild regression and result in a seemingly linear regression with a slope of less than unity. However, further calculations indicate three possible ways to use Schild analysis to detect receptor heterogeneity in tissues. One indicator of receptor heterogeneity is a change in the slope of the dose-response curve for the agonist in the presence of a selective antagonist. A second indicator would be a marked heteroscedasticity of errors in the Schild regression, i.e., the magnitude of the standard errors in the ordinate values would depend upon the concentration of the antagonist. A third, and most experimentally accessible, aspect of heterogeneous receptor systems predicts that changes in the overall sensitivity of organ response mechanisms will differentially alter the relative strength of two receptor inputs. This would be observed as a change in the potency of an antagonist. Under these circumstances, differences in the stimulus-response characteristics of a tissue would result in a change in the Schild regression for a selective antagonist. These concepts are discussed in terms of the use of Schild analysis in functional systems for the detection of physiologically relevant mixtures of receptors and the possible advantages over biochemical binding data.
本文描述了一个模型，该模型可预测在具有多种介导反应的受体的组织中竞争性拮抗剂的行为。两种受体类型的受体刺激通过细胞刺激 - 反应机制进行求和与处理，从而转化为组织反应。主要受体由标准的朗缪尔等温线描述，并添加了具有可变最大强度的次要受体输入，对于该次要受体输入，激动剂具有可变的敏感性。该系统中药物效应的预测不取决于两种刺激的组合方式，也不取决于用于计算的参数的绝对大小。该模型具有最大的灵活性，因为次要受体系统输入的大小没有药理学意义（即它们可以随激动剂内在效能、受体数量或刺激 - 反应偶联效率而变化）。针对各种次要受体输入，计算了双受体系统中选择性拮抗剂的理论希尔德回归。只要次要受体对激动剂反应有显著贡献，这些回归通常都是曲线的。这些计算数据还表明，次要受体系统生物输入的微小变化会掩盖希尔德回归中的曲率，并导致斜率小于1的看似线性的回归。然而，进一步的计算表明有三种可能的方法利用希尔德分析来检测组织中的受体异质性。受体异质性的一个指标是在存在选择性拮抗剂的情况下激动剂剂量 - 反应曲线斜率的变化。第二个指标将是希尔德回归中误差的明显异方差性，即纵坐标值中标准误差的大小将取决于拮抗剂的浓度。异质受体系统的第三个且最易于实验获取的方面预测，器官反应机制总体敏感性的变化将不同程度地改变两种受体输入的相对强度。这将表现为拮抗剂效能的变化。在这些情况下，组织刺激 - 反应特性的差异将导致选择性拮抗剂希尔德回归的变化。将根据在功能系统中使用希尔德分析来检测生理相关受体混合物以及相对于生化结合数据的可能优势来讨论这些概念。
