Giraldo J, Martín M, Campillo M, Pardo L
Department of Biostatistics, Faculty of Medicine, Universidad Autónoma de Barcelona, Spain.
Mol Pharmacol. 1992 Aug;42(2):373-81.
The previously defined sites in the histamine H2 receptor model [Mol. Pharmacol. 40:980-987 (1991)] were used to elucidate the pharmacological mechanism of action of compounds that act as antagonists at the receptor. In this model, a formate anion is used both as the negative site at which the histamine cation is anchored to the receptor and as a proton acceptor site. An ammonium cation is used as a proton donor site. The proposed model of recognition of cimetidine, tiotidine, and ranitidine suggests that the monocationic form of the antagonists is the most favorable species to bind the receptor. Moreover, the mode of recognition follows the same trends obtained for compounds that act as agonists; the protonated site of the molecule, i.e., imidazolium in cimetidine, guanidinium in tiotidine, or substituted ammonium in ranitidine, anchors at the negative site of the receptor, whereas the nonbasic part, i.e., cyanoguanidine in cimetidine and tiotidine and nitrodiaminoethene in ranitidine, is located between the proton donor and acceptor sites. An energetic analysis of the interaction between the antagonists and the receptor model, including the energies of ligand desolvation, shows that histamine cannot compete effectively with cimetidine, tiotidine, or ranitidine for binding to the H2 receptor. The predicted order of antagonist potencies, based on differences of formation enthalpies (delta delta H1), reproduces qualitatively the experimental rank order.
组胺H2受体模型[《分子药理学》40:980 - 987(1991)]中先前定义的位点被用于阐明作为该受体拮抗剂的化合物的药理作用机制。在这个模型中，甲酸根阴离子既作为组胺阳离子锚定到受体的负性位点，又作为质子受体位点。铵阳离子用作质子供体位点。西咪替丁、替奥替丁和雷尼替丁的识别模型表明，拮抗剂的单阳离子形式是与受体结合的最有利形式。此外，识别模式与作为激动剂的化合物所呈现的趋势相同；分子的质子化位点，即西咪替丁中的咪唑鎓、替奥替丁中的胍鎓或雷尼替丁中的取代铵，锚定在受体的负性位点，而非碱性部分，即西咪替丁和替奥替丁中的氰基胍以及雷尼替丁中的硝基二氨基乙烯，则位于质子供体和受体位点之间。对拮抗剂与受体模型之间相互作用的能量分析，包括配体去溶剂化的能量，表明组胺在与H2受体结合时无法有效地与西咪替丁、替奥替丁或雷尼替丁竞争。基于生成焓差异(ΔΔH1)预测的拮抗剂效价顺序，定性地再现了实验排序。
