Hennies H H, Günzler W A, Flohé L
Arzneimittelforschung. 1984;34(11):1471-80.
The influence of 2-(2-oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1, 1-dioxide (supidimide), a representative of a new class of sedative drugs, on the noradrenergic, dopaminergic, serotoninergic and gamma-aminobutyric acid (GABA)ergic neuronal systems of rodent brains was investigated. In each case the brain transmitter levels after administration of supidimide were determined. Utilisation of noradrenaline (norepinephrine, NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) was also investigated ex vivo. The study was complemented with in vitro investigations of biosynthesis, synaptosomal uptake, degradation, and receptor binding of the transmitters. Based on a preliminary study of the distribution of [35S]-supidimide in rat brain, in vitro effects observed at greater than 10(-4) mol/l were considered irrelevant. Similarly, in vivo effects requiring dosages higher than 300 mg/kg i.p. were not regarded adequate to explain the sedative and antiaggressive efficacy of supidimide. With the above restrictions, the following parameters can be rated as not influenced by supidimide: levels of tryptophan in rat brain and serum (free and total); 5-HT biosynthesis in vivo (rat brain; 5-HT accumulation after monoamine oxidase (MAO) blockade); activity of MAO-A and MAO-B (rat brain mitochondria); uptake of 5-HT, NE and DA (rat synaptosomes); 5-HT receptor binding ( [3H]-LSD binding assay in rat cortical membranes); tyrosine hydroxylase activity (rat adrenal glands); catechol-O-methyl transferase (COMT) (rat liver); NE binding to central alpha 1- and alpha 2-receptors (rat brain; radioligand assay with [3H]-dihydroergocryptine, [3H]-prazosin and [3H]-WB 4101 (2',6'-dimethoxy-(G-3H]-phenoxy]-ethylaminomethylbenzo-1,4-dioxane ); DA levels (whole rat brain and striata); dihydroxyphenylacetic acid (DOPAC) levels (whole rat brain without cerebellum and striata); elevated DOPAC levels after pretreatment with haloperidol; DA-dependent adenylate cyclase in vitro (rat striatum); D2 receptor binding ( [3H]-spiperone binding assay, rat striatum); GABA levels (mouse brain); GABA transaminase activity (mouse brain stem); sodium-independent [3H]-GABA receptor binding (rat brain) and benzodiazepine binding (rat cortical membranes, [3H]-diazepam binding assay). Two effects on the GABAergic system were induced by supidimide. Starting at 300 mg/kg i.p., supidimide slowed down the GABA accumulation in brains of aminooxyacetate-treated mice. At 10(-4) mol/l supidimide caused a significant inhibition of GABA uptake (rat synaptosomes).(ABSTRACT TRUNCATED AT 400 WORDS)
研究了新型镇静药物代表物2-(2-氧代-3-哌啶基)-1,2-苯并异噻唑啉-3-酮-1,1-二氧化物（舒必利胺）对啮齿动物脑内去甲肾上腺素能、多巴胺能、5-羟色胺能和γ-氨基丁酸（GABA）能神经元系统的影响。每种情况下均测定了舒必利胺给药后脑内递质水平。还对去甲肾上腺素（去甲肾上腺素，NE）、多巴胺（DA）和5-羟色胺（5-HT）的利用情况进行了离体研究。该研究还辅以对递质的生物合成、突触体摄取、降解及受体结合的体外研究。基于对[35S]-舒必利胺在大鼠脑内分布的初步研究，大于10(-4)mol/L时观察到的体外效应被认为无关紧要。同样，腹腔注射剂量高于300mg/kg时的体内效应也不足以解释舒必利胺的镇静和抗攻击功效。在上述限制条件下，以下参数可被认为不受舒必利胺影响：大鼠脑和血清中色氨酸水平（游离和总水平）；体内5-HT生物合成（大鼠脑；单胺氧化酶（MAO）阻断后5-HT积累）；MAO-A和MAO-B活性（大鼠脑线粒体）；5-HT、NE和DA摄取（大鼠突触体）；5-HT受体结合（大鼠皮质膜[3H]-麦角酰二乙胺结合试验）；酪氨酸羟化酶活性（大鼠肾上腺）；儿茶酚-O-甲基转移酶（COMT）（大鼠肝脏）；NE与中枢α1和α2受体结合（大鼠脑；用[3H]-二氢麦角隐亭、[3H]-哌唑嗪和[3H]-WB 4101（2',6'-二甲氧基-(G-3H]-苯氧基]-乙基氨基甲基苯并-1,4-二恶烷）进行放射性配体试验）；DA水平（全大鼠脑和纹状体）；二羟基苯乙酸（DOPAC）水平（全大鼠脑，不含小脑和纹状体）；氟哌啶醇预处理后DOPAC水平升高；体外DA依赖性腺苷酸环化酶（大鼠纹状体）；D2受体结合（[3H]-螺哌隆结合试验，大鼠纹状体）；GABA水平（小鼠脑）；GABA转氨酶活性（小鼠脑干）；非钠依赖性[3H]-GABA受体结合（大鼠脑）和苯二氮䓬结合（大鼠皮质膜，[3H]-地西泮结合试验）。舒必利胺对GABA能系统产生了两种效应。腹腔注射剂量从300mg/kg开始，舒必利胺减缓了氨基氧乙酸处理小鼠脑内GABA的积累。在10(-4)mol/L时，舒必利胺显著抑制了GABA摄取（大鼠突触体）。（摘要截短于400字）
