This study compares the lipid membrane interactions of indacaterol, an ultra long acting beta-2 agonist that is given once a day, to salmeterol, a twice a day beta-2 agonist, in order to elucidate the potential mechanisms leading to their different pharmacological properties. Salmeterol but not indacaterol perturbed dimyristoyl-phosphatidylcholine membranes. While the liposome partitioning of the two compounds was similar, independent of the lipid composition, the membrane affinity of indacaterol was two-fold greater than that of salmeterol when rafts, i.e. detergent-insoluble membrane domains, were used as the partition phase. The observed association kinetics with immobilized liposomes at physiological pH were two times faster for indacaterol than for salmeterol. A new model to explain the relationships between the drug/membrane interactions and drug's pharmacological properties considering multiple factors is proposed. The synergy between the higher partitioning of indacaterol into the raft micro domains and the faster membrane permeation of indacaterol could explain the faster onset and longer duration of therapeutic effect of indacaterol. The higher fluidizing effect of salmeterol on membrane fluidity may contribute to its lower intrinsic efficacy compared to indacaterol.

译文

:这项研究比较了每天服用一次的超长效β-2激动剂茚达特罗与一天两次的β-2激动剂沙美特罗之间的脂膜相互作用,以阐明导致它们不同药理作用的潜在机制特性。沙美特罗,但不是茚达特罗,不会干扰二肉豆蔻酰基磷脂酰胆碱膜。尽管两种化合物在脂质体上的分配是相似的,但与脂质组成无关,但当将筏(即洗涤剂不溶性膜结构域)用作分配相时,茚达特罗的膜亲和力比沙美特罗大两倍。茚达特罗在生理pH下观察到的与固定化脂质体的缔合动力学比沙美特罗快两倍。提出了一种新的模型,该模型考虑了多种因素,解释了药物/膜相互作用与药物药理特性之间的关系。茚达特罗在木筏微区中的较高分配与茚达特罗的较快膜渗透之间的协同作用可以解释茚达特罗起效更快,疗效持续时间更长的原因。与茚达特罗相比,沙美特罗对膜流动性的较高流化作用可能导致其较低的内在功效。

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