INHIBITION OF NEURONAL UPTAKE OF BIOGENIC-H-3 AMINES INTO RAT CEREBRAL-CORTEX BY PARTIALLY AND FULLY SATURATED DERIVATIVES OF IMIPRAMINE AND DESIPRAMINE .3. IMPORTANCE OF THE AROMATIC RING IN ADRENERGIC AMINES
INHIBITION OF NEURONAL UPTAKE OF BIOGENIC-H-3 AMINES INTO RAT CEREBRAL-CORTEX BY PARTIALLY AND FULLY SATURATED DERIVATIVES OF IMIPRAMINE AND DESIPRAMINE .3. IMPORTANCE OF THE AROMATIC RING IN ADRENERGIC AMINES
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DOI：
10.1016/0006-2952(79)90108-4
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发表时间：
1979-01-01
影响因子：
5.8
通讯作者：
RUTLEDGE, CO
中科院分区：
文献类型：
--
作者：
GRUNEWALD, GL;REITZ, TJ;RUTLEDGE, CO
为了评估芳香环在抑制三环类抗抑郁药物产生的神经元胺摄取中的重要性，制备了丙咪嗪（IMI）和地昔帕明（DMI）的衍生物，其中芳香环之一（IMIH，DMIH）或两者（IMIH2，DMIH2）完全还原为环己烷环。测定了这些化合物抑制大鼠大脑皮层切碎组织摄取l-[3H]-去甲肾上腺素(NE)、[3H]-多巴胺(DA)和[3H]-5-羟色胺(5-HT)的相对能力。一个或两个芳环的还原没有显着改变由IMI或DMI产生的[3H]-DA或[3H]5-HT的摄取抑制(IC50[中值抑制浓度]值为25-80μM)。 1个或两个环的饱和消除了DMI抑制NE摄取的选择性(IC50 0.12μM)，分别降低效力150倍(IC50 18.3μM)和250倍(IC50 29.4μM)。芳香环还原对 IMI 诱导的 NE 摄取抑制的影响不太明显。结果表明DMI或IMI与DA或5-HT摄取位点的相互作用涉及疏水性而非π电子吸引力。 DMI减少后抑制NE摄取的选择性的丧失可能反映了DMI与NE摄取位点结合中π-电子相互作用的丧失，或者可能反映了相对于在DA或5-HT胺摄取位点处发现的药物疏水结合区域的空间分布的敏感性增加。
In order to assess the importance of the aromatic rings in inhibition of neuronal amine uptake produced by tricyclic antidepressant drugs, derivatives of imipramine (IMI) and desipramine (DMI) were prepared in which either one (IMIH, DMIH) or both (IMIH2, DMIH2) of the aromatic rings were fully reduced to cyclohexane rings. The relative abilities of these compounds to inhibit the uptake of l-[3H]-norepinephrine (NE), [3H]-dopamine (DA) and [3H]-5-hydroxytryptamine (5-HT) into chopped tissue of rat cerebral cortex were determined. Reduction of one or both aromatic rings did not alter significantly the inhibition of uptake of [3H]-DA or [3H]5-HT produced by either IMI or DMI (IC50 [median inhibitory concentration] values 25-80 .mu.M). Saturation of 1 or both rings abolished the selectivity of DMI for inhibition of NE uptake (IC50 0.12 .mu.M), decreasing potency 150-fold (IC50 18.3 .mu.M) and 250-fold (IC50 29.4 .mu.M), respectively. The effect of aromatic ring reduction on the IMI-induced inhibition of NE uptake was much less pronounced. The results suggest that hydrophobic rather than .pi.-electron attractive forces are involved in the interaction of DMI or IMI with DA or 5-HT uptake sites. The loss of selectivity for inhibition of NE uptake upon reduction of DMI may reflect loss of .pi.-electron interactions in the binding of DMI to the NE uptake site or may reflect increased sensitivity to spatial disposition of the hydrophobic binding areas of the drug relative to that found at the DA or 5-HT amine uptake sites.