SPARE RECEPTORS AND INTRINSIC ACTIVITY - STUDIES WITH D-1 DOPAMINE-RECEPTOR AGONISTS

The intrinsic activities of selected dopamine D-1 receptor agonists we re 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 a mong agonists. Dihydrexidine (DHX), a potent full agonist with dramati c antiparkinsonian actions, displayed intrinsic activity similar to do pamine in all three cell lines. In contrast, SKF82958 and SKF38398 (fu ll and partial agonists, respectively, in rat striatum) had intrinsic activities equal to dopamine in GH(4) cells that expressed a high dens ity of D-1 receptors, yet were of lower intrinsic activity in C-6 cell s having 15-fold fewer receptors. The idea that spare receptors are on e important determinant of observed intrinsic activity was explored di rectly by ''receptor titration,'' in which ca. 90% of D-1 receptors in Ltk cells were inactivated using EEDQ, an irreversible antagonist. Wh ereas EEDQ pretreatment decreased the potency of all agonists, it chan ged 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 mea ningful 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 im portant predictor of the clinical utility Of D-1 agonists. (C) 1995 Wi ley-Liss, Inc.