Reggio P, Topiol S, Weinstein H
J Med Chem. 1986 Nov;29(11):2412-5. doi: 10.1021/jm00161a047.
A model for drug action at the histamine H2-receptor has been evaluated computationally for the agonists 2- and 4-methylhistamine. Based on molecular properties calculated for molecular structures optimized with ab initio quantum mechanical methods, the activities of these compounds and their potencies relative to histamine are found to be explained by the previously proposed model. Recognized in the N3-H tautomeric form of their monocations, both compounds exhibit a change in ring tautomeric preference when the cationic side chain is neutralized. This change makes possible their participation in a proposed proton relay event that was postulated to initiate the receptor response of H2-agonists. The relative concentrations of the mono- and dication forms of the molecules in equimolar concentrations of histamine and the two derivatives are calculated from the values of the molecular electrostatic potentials at the ring protonation sites. Because the monocation is the species recognized at the H2-receptor, the reduced potency of 2-methylhistamine relative to histamine and to the 4-methyl derivative is explained by the finding that 2-methylhistamine will have the lowest concentration of the recognized species. The rank order of potencies obtained from the ratio of monocationic species of the molecules is in agreement with experimental results.
已通过计算评估了组胺H2受体上激动剂2-甲基组胺和4-甲基组胺的药物作用模型。基于用从头算量子力学方法优化的分子结构计算出的分子性质，发现这些化合物的活性及其相对于组胺的效价可用先前提出的模型来解释。两种化合物以其单阳离子的N3-H互变异构形式存在，当阳离子侧链被中和时，它们的环互变异构偏好都会发生变化。这种变化使它们有可能参与一个假定的质子传递事件，该事件被认为是引发H2激动剂受体反应的起始步骤。根据环质子化位点处分子静电势的值，计算出组胺和两种衍生物等摩尔浓度下分子单阳离子和双阳离子形式的相对浓度。由于单阳离子是在H2受体上被识别的物种，2-甲基组胺相对于组胺和4-甲基衍生物效价降低的原因是，2-甲基组胺具有最低浓度的被识别物种。从分子单阳离子物种比例获得的效价顺序与实验结果一致。
