Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse.
Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse.
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第二代多巴胺转运蛋白选择性苯托品类似物的群体药代动力学、脑分布和药效学被开发为治疗可卡因滥用的潜在替代疗法。
DOI：
10.1002/jps.21123
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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：
Syed,ShariqA;Newman,AmyH;Othman,AhmedA;Eddington,NatalieD
第二代N-取代的3α-[双（4′-氟苯基）甲氧基]-托烷（GA 1-69、JHW 005和JHW 013）与多巴胺转运蛋白（DAT）具有高亲和力，与毒蕈碱受体结合（M1）相比，对DAT具有高度选择性。本研究的目的是表征三种新型N-取代苯扎托品（BZT）类似物在雄性Sprague-Dawley大鼠中的脑分布、药代动力学和药效学[细胞外脑多巴胺（DA）水平]。BZT类似物具有较高的分布（Vd= 8.69-34.3vs. 0.9 L/kg）沿着更长的消除时间（t1/2：4.1-5.4vs. 0.5（h）比以前报告的可卡因。脑-血浆分配系数为1.3-2.5vs。2.1可卡因在评价的最高剂量下，BZT类似物对细胞外脑（DA）水平的影响范围从最小影响（GA 1-69）到数倍升高（JHW 013为基础DA的约850%）。与可卡因相比，BZT类似物的PK/PD分析结果显示其IC 50值较低，表明其抑制DA再摄取的效力更高（0.1-0.3vs. 0.7 mg/L）的浓度。与可卡因相比，这些BZT类似物具有显著不同的PK和PD特征，这表明有必要进一步评价作为可卡因滥用治疗剂。
A second generation ofN-substituted 3α-[bis(4′-fluorophenyl)methoxy]-tropanes (GA 1–69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novelN-substituted benztropine (BZT) analogs in male Sprague–Dawley rats. The BZT analogs displayed a higher distribution (Vd= 8.69–34.3vs. 0.9 L/kg) along with longer elimination (t1/2: 4.1–5.4vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3–2.5vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1–69) to several fold elevation (~850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure–response data resulted in lower IC50values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1–0.3vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted.