SK&F 89124, A POTENT AND SELECTIVE AGONIST AT PREJUNCTIONAL DOPAMINE RECEPTORS

Abstract

SK&F 89124 (4-[2-(N,N-di-n-propylamino)ethyl]-7-hydroxy-2(3H) indolone) can be considered as a derivative of N,N-di-n-propyldopamine (DPDA) in which the meta-hydroxyl is replaced by a cyclic amide function. SK&F 89124 is at least one order of magnitude more potent than DPDA as an agonist at peripheral inhibitory prejunctional dopamine receptors (DA2 receptors) in the isolated perfused rabbit ear artery. A potent agonist action of SK&F 89124 at the DA2 receptor can also be demonstrated by inhibition of radioactive overflow from prelabelled canine coronary artery or saphenous vein, and in the anesthetized dog as an inhibition of the tachycardia induced by cardioaccelerator nerve stimulation or the increase in hind-limb perfusion pressure induced by stimulation of the lumbar sympathetic chain. SK&F 89124 is a potent inhibitor of the binding of [3H]spiroperidol to D2 receptors in bovine pituitary homogenates. High concentrations of SK&F 89124 do not activate the adenylate cyclase D1 receptor in rat caudate homogenates, nor produce activation of alpha 2-adrenoceptors or H2-histamine receptors in the guinea pig atrium. Although some alpha 1-adrenoceptor mediated vasoconstriction is produced in the rabbit ear artery and rabbit aorta, the concentrations required are several orders of magnitude higher than those active at the DA2 receptor. From these data it is evident that this structural modification can increase both the potency and selectivity of DPDA as a DA2 receptor agonist. The potency and selectivity of SK&F 89124 make this agent a useful tool for determination of the functional role of the DA2 receptor.

Pharmacological evidence for the presence of a peripheral postjunctional D2‐like dopamine receptor in rabbit splenic artery

“…The D 2 ‐like agonist SKF 89124 (Figure 6), per se , was not able to produce any vasorelaxant effect up to 10 μM, unlike dopamine on the same preparations (pD 2 = 6.01 ± 0.05), but in the presence of YM 09151‐2, SKF 89124 induced a 40% relaxation at 10 μM, a concentration at which the compound probably begins to interact with D 1 ‐like receptors (Hieble et al , 1989).…”