The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse.
The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse.
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新型 N-取代苯托品类似物 GA2-50 具有有利于可卡因滥用候选替代药物的药代动力学和药效学特征。
DOI：
10.1002/jps.21389
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发表时间：
2008
影响因子：
3.8
通讯作者：
Eddington,NatalieD
中科院分区：
文献类型：
--
作者：
Othman,AhmedA;Newman,AmyH;Eddington,NatalieD
GA2-50是一种新型的N取代苯并托品类似物，对多巴胺转运蛋白具有更高的效力和选择性。GA2-50的药代动力学和药效学特性是其作为可卡因滥用替代药物的临床前评价的一部分。在大鼠体内进行了体外转运和代谢研究以及药代动力学研究。用脑内微透析法观察GA2-50对伏核外核多巴胺水平的影响以及对可卡因引起的多巴胺升高的影响。尽管GA2-50是一种P-糖蛋白底物，但仍表现出高的跨细胞通透性。在体内，GA2-50具有较高的脑摄取能力(Ri∼ 10)、较大的分布体积(Vss= 37 /kg)和较长的消除半衰期(tç= 19 h)。GA2-50在5 mg/kg和10 mg/kg静脉注射时使多巴胺分别增加1.6和2.7倍。剂量。与之前观察到的可卡因相比，GA2-50诱导的多巴胺升高显著减少，速度更慢，持续时间更长。GA2-50对可卡因同时给药引起的多巴胺升高无明显影响。本研究的结果表明，GA2-50具有作为可卡因滥用的替代药物所追求的几种属性。©2008 Wiley-Liss，Inc.和美国药剂师协会J医药科学
GA2‐50 is a novelN‐substituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2‐50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse.In vitrotransport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2‐50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2‐50 showed high transcellular permeability despite being a P‐glycoprotein substrate. GA2‐50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values.In vivo, GA2‐50 showed high brain uptake (Ri∼ 10), large volume of distribution (Vss= 37 L/kg), and long elimination half‐life (t½= 19 h). GA2‐50 resulted in 1.6‐ and 2.7‐fold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2‐50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2‐50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2‐50 possesses several attributes sought after for a substitute medication for cocaine abuse. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci