Spare receptors and intrinsic activity: Studies with D 1 dopamine receptor agonists

The intrinsic activities of selected dopamine D 1 receptor agonists were compared in three distinct molecular expression systems, C‐6, Ltk, and GH 4 , cells transfected with primate D 1A 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 GH 4 , cells that expressed a high density of D 1 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 D 1 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 D 1 agonists. © 1995 Wiley‐Liss, Inc.