Martin Renee S, Henningsen Robert A, Suen Alexander, Apparsundaram Subbu, Leung Becky, Jia Zhongjiang, Kondru Rama K, Milla Marcos E
Departments of Biochemical Pharmacology, Roche Pharmaceuticals, Palo Alto CA 94304, USA.
J Pharmacol Exp Ther. 2008 Dec;327(3):991-1000. doi: 10.1124/jpet.108.142307. Epub 2008 Sep 18.
Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [(3)H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26 degrees C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal . mol(-1)), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (DeltaH(O)) and entropy (-TDeltaS(O)) contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% DeltaG(O)) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.
几种5-羟色胺再摄取抑制剂正在临床上用于治疗抑郁症和焦虑症。然而，迄今为止，关于这些配体的药理学差异报道主要集中在它们对5-羟色胺转运体的平衡结合亲和力上。本研究使用[³H]S-西酞普兰通过放射性配体结合试验重新审视抗抑郁药的结合模式，以确定多个温度下的平衡和动力学速率常数。在26℃下观察到的所有分子的解离速率常数都落在一个狭窄的范围内。相反，结合速率常数通常随着平衡结合亲和力的增加而降低。与此一致的是，测得的S-西酞普兰结合的活化能相对较大（19.5千卡·摩尔⁻¹），表明配体结合时发生了构象变化。对于大多数药物，包括西酞普兰，通过范特霍夫分析确定反应能量学中的焓（ΔH⁰）和熵（-TΔS⁰）贡献大致相当（25-75%ΔG⁰），并且与药物的极性表面积相关（与焓呈正相关）。然而，氟伏沙明药物的结合主要是由熵驱动的。当结合这些配体的物理化学性质来考虑这些数据时，可以提出两种不同的结合模式。西酞普兰型结合模式可能使用一个极性结合口袋，该口袋允许配体与受体之间进行带电或极性相互作用，由于脱水导致的焓损失相对较小。氟伏沙明型结合模式是由将疏水性配体部分埋入一个足够灵活以使其因构象限制而导致的熵损失最小的结合口袋时释放的能量所驱动的。
