Antagonists that differentiate between ?2A- and ?2D-adrenoceptors

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Abstract
Four antagonists were examined for their ability to differentiate α2A from the orthologous α2Dadrenoceptors. The antagonists were (2S,12bS) 1′, 3′-di-methylspiro(1, 3, 4, 5′, 6, 6′, 7,12b-octahydro-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 and benoxathian. The α2-autoreceptors in rabbit brain cortex were chosen as α2A- and the a2-autoreceptors in guinea-pig brain cortex as α2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, α2-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14,304) was used as an α2-adrenoceptor agonist. UK 14, 304 decreased the stimulation-evoked overflow of tritium. The antagonists shifted the concentration-inhibition curve of UK 14, 304 to the right in an apparently competitive manner. Dissociation constants of the antagonists were calculated from the shifts. MK 912, RX 821002 and efaroxan had markedly higher affinity for (guinea-pig) α2D-adrenoceptors (pK d values 10.0, 9.7 and 9.1, respectively) than for (rabbit) α2A-adrenoceptors (pK d 8.9, 8.2 and 7.6, respectively). Benoxathian had higher affinity for α2A- (pK d 7.4) than for α2D-adrenoceptors (pK d 6.9). Ratios calculated from the K d values of the four compounds differentiated between α2A and α2D up to 100 fold. It is concluded that MK 912, RX 821002, efaroxan and benoxathian are antagonists with high power to differentiate α2A- from α2D-adrenoceptors.

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