COCAINE INHIBITION OF LIGAND-BINDING AT DOPAMINE, NOREPINEPHRINE AND SEROTONIN TRANSPORTERS - A STRUCTURE-ACTIVITY STUDY
COCAINE INHIBITION OF LIGAND-BINDING AT DOPAMINE, NOREPINEPHRINE AND SEROTONIN TRANSPORTERS - A STRUCTURE-ACTIVITY STUDY
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DOI：
10.1016/0024-3205(90)90132-b
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发表时间：
1990-01-01
期刊：
影响因子：
6.1
通讯作者：
KUHAR, MJ
中科院分区：
文献类型：
--
作者：
RITZ, MC;CONE, EJ;KUHAR, MJ
可卡因和类似物结合在多巴胺，去甲肾上腺素和5-羟色胺转运蛋白的结构-活性关系进行了测定。配体与这些位点中的每一个结合的共价键抑制对左旋异构体具有立体特异性要求。然而，涉及N-取代，C2和C3取代基修饰的可卡因衍生物的结合效力揭示了可卡因在转运体结合的结构-活性关系的差异。去除N-甲基基团在去甲肾上腺素和5-羟色胺转运蛋白位点的结合效力几乎没有变化。在C2取代基的结构变化产生的多巴胺转运蛋白的结合效力的变化，这是一般相似的方向，但不一定在去甲肾上腺素和5-羟色胺转运蛋白的幅度。对C3取代基的修饰，特别是羟基部分的取代，在去甲肾上腺素和5-羟色胺转运蛋白上产生亲和力的变化，其比在多巴胺转运蛋白上观察到的亲和力大得多。在一般情况下，我们的研究结果表明，独特的结构要求存在于每个转运网站，但可卡因结合在去甲肾上腺素和多巴胺转运蛋白可以描述更相似的结构-活性关系比5-羟色胺转运蛋白。可卡因与多巴胺转运蛋白结合的要求（我们先前已经证明与可卡因的增强作用有关）包括左旋立体特异性、C3处的β环、托烷环的至少一些部分和β环中C2甲酯基团的存在。构象
Structure-activity relationships for cocaine and analog binding at the dopamine, norepinephrine and serotonin transporters were determined. Cocaine inhibition of ligand binding to each of these sites has a stereospecific requirement for the levorotatory isomer. Binding potencies of cocaine derivatives involving N-substitution, C2 and C3 substituent modifications, however, revealed differences in structure-activity relationships for cocaine binding at the transporters. Removal of the N-methyl groups produced little change in binding potency at norepinephrine and serotonin transporter sites. Changes in structure at the C2 substituent produced changes in binding potency at the dopamine transporter which were generally similar in direction, but not necessarily in magnitude at the norepinephrine and serotonin transporters. Modifications to the C3 substituent, especially substitution of a hydroxyl moiety, produce changes in affinity at norepinephrine and serotonin transporters which are much larger than those observed at dopamine transporters. In general, our results indicate that unique structural requirements exist for each transporter site, but that cocaine binding at norepinephrine and dopamine transporters can be described by more similar structure-activity relationships than those found for the serotonin transporter. Requirements for cocaine binding to the dopamine transporter, which we have previously shown to be associated with the reinforcing effects of cocaine, include levorotatory stereospecificity, the because ring at C3, at least some portions of the tropane ring, and the presence of the C2 methyl ester group in the .beta. conformation.