The alleged dopamine D-1 receptor agonist SKF 83959 is a dopamine D-1 receptor antagonist in primate cells and interacts with other receptors

So far, no clear correlation has been found between the effects of dopamine D-1 receptor agonists on motor behavior in primate models of Parkinson's d isease and their ability to stimulate adenylate cyclase in rats, the benzaz epine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-t etrahydro-]H-3-benzazepine) being the most striking example. Since this dis crepancy might be attributed to: (A) the different species used to study th ese effects or (B) the interaction of SKF 83959 with other catecholamine re ceptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells eq uipped with dopamine D-1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors . Binding studies revealed that SKF 83959 displayed the highest affinity fo r the dopamine D-1 receptor (pK(i) = 6.72) and the alpha(2)-adrenoceptor (p K(i) = 6.41) and moderate affinity for the dopamine D-2 receptor and the no radrenaline transporter. In monkey and human cells, SKF 83959 did not stimu late cyclic adenosine monophosphate (cAMP) formation to a significant exten t, but antagonized very potently the dopamine-induced stimulation of cAMP f ormation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concent rations > 10 mu M. Finally, SKF 83959 concentration dependently increased e lectrically evoked noradrenaline release, indicating that it had alpha(2)-a drenoceptor blocking activity and interfered with the noradrenaline transpo rter. In conclusion, SKF 83959 is a potent dopamine D-1 receptor and alpha( 2)-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 8395 9 in primates are not mediated by striatal dopamine D-1 receptors coupled t o adenylate cyclase in a stimulatory way. (C) 1999 Elsevier Science B.V. Al l rights reserved.