Thomas D R, Nelson D R, Johnson A M
Beecham Pharmaceuticals Research Division, Harlow, Essex, UK.
Psychopharmacology (Berl). 1987;93(2):193-200. doi: 10.1007/BF00179933.
Paroxetine was shown to be a potent (Ki = 1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED50 = 1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED50 greater than 30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED50 1-3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine has little affinity for alpha 1, alpha 2 or beta adrenoceptors, dopamine (D2), 5-HT1, 5-HT2 or histamine (H1) receptors at concentrations below 1000 nM. Paroxetine demonstrated weak affinity for muscarinic receptors (Ki = 89 nM) but was at least 15 fold weaker than amitriptyline (Ki = 5.1 nM). Paroxetine, therefore, provides a useful pharmacological tool for investigating 5-HT systems and furthermore should be an antidepressant with reduced tricyclic-like side-effects.
在体外实验中，帕罗西汀被证明是一种强效（Ki = 1.1 nM）且特异性的[3H]-5-羟色胺（5-HT）摄取到大鼠皮质和下丘脑突触体中的抑制剂。Lineweaver-Burk动力学分析确定这种抑制本质上是竞争性的，这意味着它与5-HT摄取转运体复合物直接相互作用。口服帕罗西汀会对离体大鼠下丘脑突触体中[3H]-5-HT的摄取产生剂量相关的抑制作用（ED50 = 1.9 mg/kg），而对[3H]-去甲肾上腺素（NA）的摄取影响很小（ED50大于30 mg/kg）。口服给药14天后，这种对5-HT摄取的选择性得以维持。帕罗西汀（ED50 1 - 3 mg/kg口服）可预防对氯苯丙胺（PCA）在大鼠脑中的5-HT耗竭作用，表明其在体内具有5-HT摄取阻断作用。体外大鼠脑的放射性配体结合技术表明，在浓度低于1000 nM时，帕罗西汀对α1、α2或β肾上腺素能受体、多巴胺（D2）、5-HT1、5-HT2或组胺（H1）受体几乎没有亲和力。帕罗西汀对毒蕈碱受体表现出较弱的亲和力（Ki = 89 nM），但至少比阿米替林（Ki = 5.1 nM）弱15倍。因此，帕罗西汀为研究5-HT系统提供了一种有用的药理学工具，而且应该是一种具有减少三环类药物样副作用的抗抑郁药。
