Li J G, Raffa R B, Cheung P, Tzeng T B, Liu-Chen L Y
Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Eur J Pharmacol. 1998 Aug 7;354(2-3):227-37. doi: 10.1016/s0014-2999(98)00444-0.
The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid receptor stably expressed in Chinese hamster ovary (CHO) cells were investigated. For every ligand, the Kd or Ki values at 0 degrees C, 12 degrees C, 25 degrees C and 37 degrees C were determined, a van't Hoff plot was generated and deltaH degrees' , deltaS degrees' and -TdeltaS degrees' and deltaG degrees' were calculated. Changes in free energy (deltaG degrees') ranged from -10.35 to -15.65 kcal/mol. The binding of sufentanil, ohmefentanyl, diprenorphine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamineThr-NH2 (CTAP) was endothermic (deltaH degrees' > 0) and driven by an increase in entropy (-TdeltaS degrees' = -13.08 to -18.57 kcal/mol). The binding of naltrexone was exothermic (deltaH degrees' = -12.56 kcal/mol) and essentially enthalpy-driven. The binding of morphine, methadone, pentazocine, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) was exothermic (deltaH degrees' = -3.53 to -9.95 kcal/mol) and occurred with an increase in entropy (-TdeltaS degrees' = -2.48 to -7.92 kcal/mol). Plots of enthalpy versus entropy and enthalpy versus free energy were linear, although enthalpy-entropy compensation was not evident. The entropy changes were not correlated with apparent lipophilicity of the compounds. These results suggest that: (1) opioid ligands bind to the mu receptor by specific mechanisms, unrelated to lipid solubility; (2) the mechanism of binding is not universally different for peptide and non-peptide ligands; (3) the nature of binding does not a priori determine intrinsic activity. The results reveal a novel differentiation of opioid ligands into two groups (group 1: ohmefentanyl, sufentanil, diprenorphine, CTAP and PL017; group 2: naltrexone, morphine, methadone, DAMGO, pentazocine), based on two distinct relationships between enthalpy versus free energy of binding, the details of which are yet to be elucidated.
研究了十种配体与稳定表达于中国仓鼠卵巢（CHO）细胞中的克隆大鼠μ-阿片受体结合的表观热力学参数。对于每种配体，测定了0℃、12℃、25℃和37℃下的Kd或Ki值，生成了范特霍夫图，并计算了ΔH°'、ΔS°'、-TΔS°'和ΔG°'。自由能变化（ΔG°'）范围为-10.35至-15.65 kcal/mol。舒芬太尼、奥芬太尼、二丙诺啡和D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-精氨酸-苏氨酸-青霉胺苏氨酸-NH2（CTAP）的结合是吸热的（ΔH°' > 0），由熵的增加驱动（-TΔS°' = -13.08至-18.57 kcal/mol）。纳曲酮的结合是放热的（ΔH°' = -12.56 kcal/mol），基本上由焓驱动。吗啡、美沙酮、喷他佐辛、[D-丙氨酸2，N-甲基苯丙氨酸4，甘氨酸-ol]脑啡肽（DAMGO）和酪氨酸-脯氨酸-N-甲基苯丙氨酸-D-脯氨酸-NH2（PL017）的结合是放热的（ΔH°' = -3.53至-9.95 kcal/mol），且伴随着熵的增加（-TΔS°' = -2.48至-7.92 kcal/mol）。焓与熵以及焓与自由能的关系图是线性的，尽管焓-熵补偿不明显。熵的变化与化合物的表观亲脂性无关。这些结果表明：（1）阿片类配体通过与脂溶性无关的特定机制与μ受体结合；（2）肽类和非肽类配体的结合机制并非普遍不同；（3）结合的性质不能先验地决定内在活性。结果揭示了基于结合焓与自由能之间的两种不同关系，将阿片类配体分为两组（第1组：奥芬太尼、舒芬太尼、二丙诺啡、CTAP和PL017；第2组：纳曲酮、吗啡、美沙酮、DAMGO、喷他佐辛），其细节尚待阐明。
