Andringa G, Drukarch B, Leysen J E, Cools A R, Stoof J C
Research Institute Neurosciences, Department of Neurology, Vrije Universiteit, Amsterdam, Netherlands.
Eur J Pharmacol. 1999 Jan 1;364(1):33-41. doi: 10.1016/s0014-2999(98)00825-5.
So far, no clear correlation has been found between the effects of dopamine D1 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 D1 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 D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 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 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.
到目前为止，在帕金森病灵长类动物模型中，尚未发现多巴胺D1受体激动剂对运动行为的影响与其在大鼠中刺激腺苷酸环化酶的能力之间存在明确的相关性，苯并氮杂䓬类药物SKF 83959（3-甲基-6-氯-7,8-二羟基-1-[3-甲基苯基]-2,3,4,5-四氢-1H-3-苯并氮杂䓬）就是最典型的例子。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，本研究的目的是：（1）研究SKF 83959在配备多巴胺D1受体的培养的人源和猴源神经胶质细胞中刺激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D1受体（pKi = 6.72）和α2-肾上腺素能受体（pKi = 6.41）显示出最高亲和力，对多巴胺D2受体和去甲肾上腺素转运体具有中等亲和力。在猴源和人源细胞中，SKF 83959在很大程度上并未刺激环磷酸腺苷（cAMP）的生成，但在两种细胞类型中均非常有效地拮抗多巴胺诱导的cAMP生成的刺激作用。该化合物仅在浓度>10μM时才刺激基础多巴胺释放并抑制去极化诱导的乙酰胆碱释放。最后，SKF 83959浓度依赖性地增加电诱发的去甲肾上腺素释放，表明它具有α2-肾上腺素能受体阻断活性并干扰去甲肾上腺素转运体。总之，SKF 83959是一种有效的多巴胺D1受体和α2-肾上腺素能受体拮抗剂。因此，SKF 83959在灵长类动物中的抗帕金森病作用不是由以刺激性方式与腺苷酸环化酶偶联的纹状体多巴胺D1受体介导的。
