A thermodynamic approach to problems of drug antagonism. Measurements of the parameters of affinity (pA2) of antihistaminics and a beta-haloalkylamine under varying experimental conditions.
A thermodynamic approach to problems of drug antagonism. Measurements of the parameters of affinity (pA2) of antihistaminics and a beta-haloalkylamine under varying experimental conditions.
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解决药物拮抗问题的热力学方法。
DOI：
10.1016/0014-2999(74)90055-7
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发表时间：
1974
影响因子：
5
通讯作者：
F. Fernandes
中科院分区：
文献类型：
--
作者：
M. Rocha e Silva;F. Fernandes
描述了苯海拉明（Benadryl）和酚苄明（Dibenzyline）的两种pA 2测量方法（平衡时和受体部位）。对于苯海拉明，在冲洗制剂后，存在自发恢复，pA 2（在受体位点）迅速降低至0，但对于苯苄明，如果温度保持在37°C，则制剂保持高水平的抑制数小时。这样的条件允许在不同温度（从40°C下降到2-4°C）下测量亲和力参数（pA 2 = −log Ki）。通过使用经典的Arrhenius图，可以计算出酚苄明与组胺H1受体结合形成的熵（−ΔH）和熵（ΔS），发现这种结合强烈依赖于温度。在20°C以上，焓ΔH = − 21，494.8 cal/°K是显著的，并且足够大，表明共价键或离子键，具有负的生成熵。低于20°CΔH = − 3，461.04 e.u.是低的和不显著的，具有正的形成熵。结果表明，在低温下，受体与拮抗剂的结合可能是熵驱动的，更多地依赖于拮抗剂与受体位点的疏水相互作用。
Two measurements of pA2(in equilibriumandat the receptor site) are described for both diphenhydramine (Benadryl) and phenoxybenzamine (Dibenzyline). For diphenhydramine, after washing out the preparation, there is a spontaneous recovery with a rapid decrease of pA2(at the receptor site) to 0, though for phenoxybenzamine the preparation remains at a high level of inhibition for several hours, provided the temperature is kept at 37°C. Such a conditioned allowed a measurement of the affinity parameter (pA2= −log Ki) at different temperatures, from 40°C down to 2–4°C. By using a classical Arrhenius plot it was possible to calculate enthalpies (−ΔH) and entropies (ΔS) of formation of the alleged bindings of phenoxybenzamine with the histamine H1-receptor which was found to depend strongly upon temperature. Above 20°C the enthalpyΔH = −21,494.8 cal/°K was significant and large enough to suggest a covalent or ionic binding, with a negative entropy of formation. Below 20°CΔH = −3,461.04 e.u. was low and non-significant, with a positive entropy of formation. The conclusion was drawn that at low temperature the binding is probably entropy driven and depends more upon hydrophobic interactions of the antagonist with the receptor site.