DOPAMINE-D(1)-RECEPTORS - EFFICACY OF FULL (DIHYDREXIDINE) VS PARTIAL(SKF38393) AGONISTS IN PRIMATES VS RODENTS

Although partial efficacy dopamine D1 receptor agonists have little th erapeutic benefit in parkinsonism, the first high potency, full effica cy dopamine D1 receptor agonist dihydrexidine recently has been shown to have profound antiparkinsonian effects. One reason for the greater antiparkinsonian effects of dihydrexidine vs. SKF38393 might be that S KF38393, while a partial dopamine D1 receptor agonist in rodent striat al preparations, has virtually no agonist activity in monkey striatum (Pifl et al., 1991, Eur. J. Pharmacol. 202, 273). To explore this hypo thesis, we compared the dopamine D1 receptor affinity and efficacy of dihydrexidine and SKF38393 in striatum from rat and monkey. In vitro b inding studies using membranes from putamen of adult rhesus monkeys de monstrated that dihydrexidine competed for dopamine D1 receptors (labe led with [H-3]SCH23390) with high potency (IC50 = 20 nM vs. ca. 10 nM in rat brain). SKF38393 was about 4-fold less potent than dihydrexidin e in both monkey and rat brain. The in vitro functional activity of th ese drugs was assessed by their ability to stimulate adenylate cyclase activity in tissue homogenates. Dihydrexidine was of full efficacy (r elative to dopamine) in stimulating cAMP synthesis in both monkey and rat. SKF38393 was only a partial efficacy agonist in both rat striatum and monkey putamen, but contrary to the original hypothesis, it had t he same efficacy (ca. 40% relative to dihydrexidine) in membranes from both species. Interestingly, greater between-subject variation was fo und in the stimulation produced by SKF38393 in primate compared to rat brain, although the basis for this variation is unclear. The present data demonstrate for the first time that dihydrexidine is a full effic acy dopamine D1 receptor agonist in primate brain. Moreover, these dat a indicate that the partial efficacy dopamine D1 receptor agonist SKF3 8393 causes the same relative response (compared to dopamine) in rat a nd monkey dopamine D1 receptors. Together, this information suggests t hat the antiparkinsonian effect of dihydrexidine vs. the relative inac tivity of SKF38393 is not due to the fact that primate brains are simp ly unresponsive to SKF38393.