Watts V J, Lawler C P, Gonzales A J, Zhou Q Y, Civelli O, Nichols D E, Mailman R B
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill 27599-7250, USA.
Synapse. 1995 Oct;21(2):177-87. doi: 10.1002/syn.890210211.
The intrinsic activities of selected dopamine D1 receptor agonists were compared in three distinct molecular expression systems, C-6, Ltk, and GH4 cells transfected with primate D1A receptors. The influence of the cell expression system on intrinsic activity varied markedly among agonists. Dihydrexidine (DHX), a potent full agonist with dramatic antiparkinsonian actions, displayed intrinsic activity similar to dopamine in all three cell lines. In contrast, SKF82958 and SKF38393 (full and partial agonists, respectively, in rat striatum) had intrinsic activities equal to dopamine in GH4 cells that expressed a high density of D1 receptors, yet were of lower intrinsic activity in C-6 cells having 15-fold fewer receptors. The idea that spare receptors are one important determinant of observed intrinsic activity was explored directly by "receptor titration," in which ca. 90% of D1 receptors in Ltk cells were inactivated using EEDQ, an irreversible antagonist. Whereas EEDQ pretreatment decreased the potency of all agonists, it changed the intrinsic activity of some, but not all, drugs. A 40% decrease was seen with the partial agonist SKF38393, and, surprisingly, a 30% decrease was seen with the purported full agonist SKF82958. Conversely, the intrinsic activity of DHX and A68930 were unaffected by the EEDQ treatment. The data demonstrate that significant and biologically meaningful differences in intrinsic efficacy (e.g., DHX vs. SKF82958) may be obscured in test systems that have sufficient receptor reserve (e.g., the striatum). Such differences in intrinsic efficacy may be an important predictor of the clinical utility of D1 agonists.
在三种不同的分子表达系统（C-6细胞、Ltk细胞以及转染了灵长类D1A受体的GH4细胞）中比较了所选多巴胺D1受体激动剂的内在活性。细胞表达系统对内在活性的影响在不同激动剂之间有显著差异。二氢麦角隐亭（DHX）是一种具有显著抗帕金森病作用的强效完全激动剂，在所有三种细胞系中显示出与多巴胺相似的内在活性。相比之下，SKF82958和SKF38393（分别为大鼠纹状体中的完全激动剂和部分激动剂）在表达高密度D1受体的GH4细胞中具有与多巴胺相当的内在活性，但在受体数量少15倍的C-6细胞中内在活性较低。通过“受体滴定”直接探讨了备用受体是观察到的内在活性的一个重要决定因素的观点，在“受体滴定”中，使用不可逆拮抗剂EEDQ使Ltk细胞中约90%的D1受体失活。虽然EEDQ预处理降低了所有激动剂的效力，但它改变了一些（但不是所有）药物的内在活性。部分激动剂SKF38393的内在活性降低了40%，令人惊讶的是，所谓的完全激动剂SKF82958的内在活性降低了30%。相反，DHX和A68930的内在活性不受EEDQ处理的影响。数据表明，在具有足够受体储备（如纹状体）的测试系统中，内在效能的显著且具有生物学意义的差异（如DHX与SKF82958）可能会被掩盖。这种内在效能的差异可能是D1激动剂临床效用的一个重要预测指标。
