DOPAMINE RECEPTOR AGONISTS - SELECTIVITY AND DOPAMINE-D1 RECEPTOR EFFICACY
DOPAMINE RECEPTOR AGONISTS - SELECTIVITY AND DOPAMINE-D1 RECEPTOR EFFICACY
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DOI：
10.1016/0922-4106(90)90194-3
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发表时间：
1990-06-12
期刊：
影响因子：
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通讯作者：
JANSEN, JA
中科院分区：
文献类型：
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作者：
ANDERSEN, PH;JANSEN, JA
多巴胺受体的选择性进行了研究的多巴胺受体激动剂的数量。 在体外，苯并氮杂卓衍生物，SKF 38393和SKF 75670以及异喹啉衍生物SKF 89626和SKF 89615具有D1受体选择性。 所有其他化合物如阿扑吗啡、CY 208-243、6，7-ADTN和3-PPP要么是D2-选择性的，要么不能区分亚型。 一般而言，在体内观察到体外观察到的相同受体谱。 这种模式的例外是：不穿过血脑屏障的化合物，如6，7-ADTN和SKF 89626，以及在体外表现出非选择性但在体内表现出D2选择性的化合物，如阿扑吗啡，CI 201-678和CY 208-243。 详细表征了许多化合物在抑制[H-3]SCH 23390结合方面的GTP诱导亲和力变化，以及刺激大鼠纹状体腺苷酸环化酶的效价和疗效。 在不存在GTP的情况下，这些激动剂对[H-3]SCH 23390特异性结合的抑制作用发生在希尔斜率低于1的情况下，并且可以通过具有高（K（H））和低亲和力（K（L））组分的双位点模型进行最佳解释。 存在15 μ M GTP时，[H-3]SCH 23390结合受到抑制，Hill斜率为1。 在存在15 μ M GTP的情况下获得的K（I）值与在不存在GTP的情况下观察到的低亲和力组分K（L）值相似。 分析激动剂刺激腺苷酸环化酶的能力与多巴胺的关系（功效= 100%）。 苯并氮杂卓衍生物的效力从24%（SKF 75670）变化到100%（SKF 83189），取决于苯并氮杂卓核上的取代基。 异喹啉类药物SKF 89626和SKF 89615具有完全疗效，而大多数其他受试激动剂似乎仅具有部分疗效。 总之，本文介绍了一些多巴胺能激动剂在刺激腺苷酸环化酶中的多巴胺受体选择性和有效性的数据。 这些数据可能为将来多巴胺能介导的事件的表征中激动剂的选择奠定基础。
Dopamine receptor selectivity was investigated for a number of dopamine receptor agonists. In vitro, the benzazepine derivatives, e.g., SKF 38393 and SKF 75670 as well as the isoquinoline derivatives, SKF 89626 and SKF 89615, were D1 receptor-selective. All other compounds like apomorphine, CY 208-243, 6,7-ADTN and 3-PPP were either D2-selective or did not discriminate between subtypes. In general, the same receptor profile seen in vitro was observed in vivo. The exceptions to this pattern were: compounds which did not cross the blood-brain barrier, like 6,7-ADTN and SKF 89626, and compounds which appeared nonselective in vitro but demonstrated D2 selectivity in vivo like apomorphine, CI 201-678 and CY 208-243. A number of compounds were characterized in detail with respect to a GTP-induced affinity shift in inhibition of [H-3]SCH 23390 binding, and potency and efficacy in stimulating adenylate cyclase from rat striatum. Inhibition of specific [H-3]SCH 23390 binding by these agonists in the absence of GTP occurred with Hill slopes below unity and could best be explained by a two-site model with a high (K(H))- and low-affinity (K(L)) component. Inhibition of [H-3]SCH 23390 binding in the presence of 15-mu-M GTP occurred with Hill slopes of unity. The K(I) values obtained in the presence of 15-mu-M GTP were similar to the K(L) values, the low-affinity component observed in the absence of GTP. The capability of the agonists to stimulate the adenylate cyclase was analyzed in relation to dopamine (efficacy = 100%). The efficacy of the benzazepine derivatives varied from 24 (SKF 75670) to 100% (SKF 83189), dependent on the substituents on the benzazepine core. The isoquinolines, SKF 89626 and SKF 89615 had full efficacy, whereas most other agonists tested appeared to have only partial efficacy. In summary, the present paper presents data on dopamine receptor selectivity and efficacy in stimulating adenylate cyclase for a number of dopaminergic agonists. These data may create a basis for selection of agonists in future characterizations of dopaminergic-mediated events.