A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein
A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein
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DOI：
10.1016/j.xphs.2018.02.019
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发表时间：
2018-07-01
影响因子：
3.8
通讯作者：
Roberts, Arthur G.
中科院分区：
文献类型：
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作者：
Gibbs, Morgan E.;Wilt, Laura A.;Roberts, Arthur G.
P-糖蛋白（Pgp）是一种多药耐药性转运蛋白，可限制包括阿片类药物在内的多种神经治疗药物渗透到大脑中。二苯丙胺类阿片美沙酮和洛哌丁胺在结构上相似，但洛哌丁胺的Pgp介导的转运速率约高4倍。除了这些差异外，它们对Pgp介导的三磷酸腺苷（ATP）水解的影响也存在显著差异。美沙酮对Pgp介导的ATP水解的激活是双相的，而洛哌丁胺对ATP水解的激活是双相的，这意味着美沙酮在Pgp上有一个结合位点，洛哌丁胺在Pgp上有2个结合位点。这些药物和地高辛的色氨酸荧光淬灭表明阿片类药物之间存在竞争，洛哌丁胺不竞争地高辛结合位点。丙烯酰胺淬灭色氨酸荧光探针Pgp构象的变化表明，美沙酮和洛哌丁胺诱导的构象变化是不同的。这些结果被用来开发一个模型PGP介导的美沙酮和洛哌丁胺的运输阿片类药物的结合和构象变化被用来解释美沙酮和洛哌丁胺之间的阿片类药物的转运率的差异。(C)2018年美国药学协会（R）。爱思唯尔公司出版All rights reserved.
P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide. (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.