ANTAGONISTS THAT DIFFERENTIATE BETWEEN ALPHA(2A)-ADRENOCEPTORS AND ALPHA(2D)-ADRENOCEPTORS

Four antagonists were examined for their ability to differentiate alph a(2A)- from the orthologous alpha(2D)-adrenoceptors. The antagonists w ere (2S,12bS) 1', 3'-dimethylspiro(1, 3, 4, 5', 6, 6', 7, 12b-octahydr o-2H-benzo-[b]furo[2, 3-a]quinolizine)-2, 4'-pyrimidin-2'-one (MK 912) , 2-[2-(methoxy-1, 4-benzodioxanyl)imidazoline (RX 821002), efaroxan a nd benoxathian. The a,autoreceptors in rabbit brain cortex were chosen as alpha(2A)- and the alpha(2)-autoreceptors in guinea-pig brain cort ex as alpha(2D)-adrenoceptors. Slices of the brain cortex were preincu bated with H-3-noradrenaline and then superfused and stimulated electr ically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, alpha(2)-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)-quin oxaline (UK 14,304) was used as an alpha(2)-adrenoceptor agonist. UK 1 4,304 decreased the stimulation-evoked overflow of tritium. The antago nists shifted the concentration-inhibition curve of UK 14,304 to the r ight in an apparently competitive manner. Dissociation constants of th e antagonists were calculated from the shifts. MK 912, RX 821002 and e faroxan had markedly higher affinity for (guinea-pig) alpha(2D)-adreno ceptors (pK(d) values 10.0, 9.7 and 9.1, respectively) than for (rabbi t) alpha(2A)-adrenoceptors (pK(d) 8.9, 8.2 and 7.6, respectively). Ben oxathian had higher affinity for alpha(2A)-(pK(d) 7.4) than for alpha( 2D)-adrenoceptors (pK(d) 6.9). Ratios calculated from the K-d values o f the four compounds differentiated between alpha(2A) and alpha(2D) up to 100 fold. It is concluded that MK 912, RX 821002, efaroxan and ben oxathian are antagonists with high power to differentiate alpha(2A)- f rom alpha(2D)-adrenoceptors.