Drukarch B, Leysen J E, Stoof J C
Department of Neurology, Medical Faculty, Free University, Amsterdam, The Netherlands.
Life Sci. 1988;42(9):1011-7. doi: 10.1016/0024-3205(88)90431-6.
In a recent study we have documented the acetylcholinesterase and outward K+-current inhibiting activity of 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug reportedly active in the treatment of Alzheimer patients. In the present study we investigated the effects of THA on the uptake and release of radiolabeled NA, DA and 5-HT. THA concentration-dependently inhibited the uptake of these monoamines with IC-50 values of approximately 1, 7 and 2 microM respectively. Release studies of these radiolabeled monoamines from control and reserpine pretreated tissue revealed that the THA-induced uptake inhibition does not occur at the level of the axonal membrane but at the level of the monoaminergic storage granules. In addition the affinity of THA for alpha-1, alpha-2 and beta-adrenoceptors, for D-2 dopamine, S-1a and S-2 serotonin and for muscarinic receptors was investigated. It appeared that in concentrations up to 1 microM THA did not display any affinity towards these receptors. It is concluded from these experiments that the effects of THA on monoaminergic neurotransmission might contribute to the alleged therapeutic action of THA in Alzheimer's disease.
在最近的一项研究中，我们记录了9-氨基-1,2,3,4-四氢吖啶（THA）的乙酰胆碱酯酶抑制活性和外向钾电流抑制活性，据报道该药物在治疗阿尔茨海默病患者方面具有活性。在本研究中，我们研究了THA对放射性标记的去甲肾上腺素（NA）、多巴胺（DA）和5-羟色胺（5-HT）摄取和释放的影响。THA浓度依赖性地抑制这些单胺的摄取，IC50值分别约为1、7和2微摩尔。对对照组织和利血平预处理组织中这些放射性标记单胺的释放研究表明，THA诱导的摄取抑制并非发生在轴突膜水平，而是发生在单胺能储存颗粒水平。此外，还研究了THA对α-1、α-2和β-肾上腺素能受体、D-2多巴胺受体、S-1a和S-25-羟色胺受体以及毒蕈碱受体的亲和力。结果表明，在浓度高达1微摩尔时，THA对这些受体没有显示出任何亲和力。从这些实验得出的结论是，THA对单胺能神经传递的影响可能有助于其在阿尔茨海默病中所谓的治疗作用。
