The thermodynamics of agonist and antagonist binding to dopamine D-2 receptors.
The thermodynamics of agonist and antagonist binding to dopamine D-2 receptors.
复制标题
激动剂和拮抗剂与多巴胺 D-2 受体结合的热力学。
作者：
Gavin Kilpatrick;N. El Tayar;H. van de Waterbeemd;P. Jenner;B. Testa;C. Marsden
多巴胺激动剂和拮抗剂在4度、15度、26度和37度时与[~3H]螺环酮结合在大鼠纹状体膜制剂上的能力随着温度的变化而显著变化。多巴胺和多巴胺激动剂2-amino-6，7-dihydroxy-1，2，3，4-tetrahydronaphthalene氢溴酸盐(ADTN)在较低温度下作用更强。多巴胺拮抗剂氟哌啶醇、顺式氟苯硫醇、cis-N-(1-benzyl-1-methypyrrolidin-3-yl)-5-chloro-2-methoxy-9-甲氨基苯甲酰胺(YM 09151-2)、拉氯普利和氯氮平以及激动剂阿朴吗啡和培高利特与[~3H]螺环酮结合的竞争能力几乎不受温度的影响。(+)-丁拉莫尔在较高温度下效力更强。相反，拮抗剂舒必利、甲氧氯普胺、氯波必利、舒托必利、硫必利、吡喹酮和泽替多林在较低温度下更有效。多巴胺和ADTN激动剂之间的相互作用是由焓的降低驱动的，从而导致了能量上不利的熵降低。拮抗剂氟哌啶醇、顺式氟苯硫醇、YM 09151-2、拉氯普利、(+)-丁拉莫尔和氯氮平以及激动剂阿朴吗啡和培高利特的结合是由熵驱动的。舒必利、甲氧氯普胺、氯波必利、阿利沙必利、舒托必利、硫必利、吡喹酮和泽替多林与其他拮抗剂的相互作用不同于其他拮抗剂，它们的相互作用是由焓驱动的。观察到的熵变化与置换药物的亲脂性有关，而与它们的内在活性无关。
The ability of dopamine agonists and antagonists to compete with [3H]spiperone binding to rat striatal membrane preparations at 4, 15, 26, and 37 degrees varied markedly with temperature. Dopamine and the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) were more potent at lower temperatures. The ability of the dopamine antagonists, haloperidol, cis-flupenthixol, cis-N-(1-benzyl-1-methypyrrolidin-3-yl)-5-chloro-2-methoxy-9- methylaminobenzamide (YM 09151-2), raclopride, and clozapine, and of the agonists apomorphine and pergolide, to compete with [3H]spiperone binding was little altered by temperature. (+)-Butaclamol was more potent at higher temperatures. In contrast, the antagonists sulpiride, metoclopramide, clebopride, sultopride, tiapride, piquindone, and zetidoline were more potent at lower temperatures. The interaction of the agonists dopamine and ADTN was driven by a decrease in enthalpy, allowing an energetically unfavorable decrease in entropy. The binding of the antagonists, haloperidol, cis-flupenthixol, YM 09151-2, raclopride, (+)-butaclamol, and clozapine, and also of the agonists, apomorphine and pergolide, was entropy driven. The interaction of the antagonists sulpiride, metoclopramide, clebopride, alizapride, sultopride, tiapride, piquindone, and zetidoline differed from that of other antagonists in being enthalpy driven. The observed entropy changes correlated with the lipophilicity of the displacing drugs and not with their intrinsic activity.