The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors
The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors
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DOI：
10.1016/s0014-2999(98)00825-5
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发表时间：
1999-01-01
影响因子：
5
通讯作者：
Stoof, JC
中科院分区：
文献类型：
--
作者：
Andringa, G;Drukarch, B;Stoof, JC
到目前为止，还没有发现多巴胺D-1受体激动剂对帕金森病灵长类动物模型运动行为的影响与它们刺激大鼠腺苷酸环化酶的能力之间存在明显的相关性，苯并氮杂卓SKF 83959（3-甲基-6-氯-7，8-羟基-1-[3-甲基苯基]-2，3，4，5-四氢-]H-3-苯并氮杂卓）是最突出的例子。由于这种差异可能归因于：（A）用于研究这些效应的不同物种或（B）SKF 83959与其他儿茶酚胺受体的相互作用，因此本研究的目的是：（1）研究SKF 83959刺激培养的具有多巴胺D-1受体的人和猴神经胶质细胞中腺苷酸环化酶的能力，以及（2）评估SKF 83959与其他儿茶酚胺受体的亲和力和功能相互作用。结合研究表明，SKF 83959对多巴胺D-1受体（pK（i）= 6.72）和α（2）-肾上腺素受体（pK（i）= 6.41）具有最高亲和力，对多巴胺D-2受体和去甲肾上腺素转运蛋白具有中等亲和力。在猴和人细胞中，SKF 83959没有显著刺激环磷酸腺苷（cAMP）的形成，但在两种细胞类型中都能非常有效地拮抗多巴胺诱导的cAMP形成刺激。该化合物刺激基础多巴胺流出和抑制去极化诱导的乙酰胆碱释放只有在浓度> 10 μ M。最后，SKF 83959浓度依赖性地增加电诱发的去甲肾上腺素释放，表明其具有α（2）-肾上腺素受体阻断活性并干扰去甲肾上腺素转运蛋白。总之，SKF 83959是一种有效的多巴胺D-1受体和α（2）-肾上腺素受体拮抗剂。因此，SKF 83959在灵长类动物中的抗帕金森病作用不是由纹状体多巴胺D-1受体以刺激方式与腺苷酸环化酶偶联介导的。(C)1999 Elsevier Science B. V.保留所有权利。
So far, no clear correlation has been found between the effects of dopamine D-1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H-3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D-1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D-1 receptor (pK(i) = 6.72) and the alpha(2)-adrenoceptor (pK(i) = 6.41) and moderate affinity for the dopamine D-2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 mu M. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha(2)-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D-1 receptor and alpha(2)-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D-1 receptors coupled to adenylate cyclase in a stimulatory way. (C) 1999 Elsevier Science B.V. All rights reserved.