The affinity and efficacy of the selective β1‐adrenoceptor stimulant RO363 at β1‐ and β2‐adrenoceptor sites

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Abstract
1 (−)−Isoprenaline and the selective β1-adrenoceptor agonist RO363 were tested for their inotropic effects in left atrial (β1) and relaxant effects in K+-depolarized uterine (β2) preparations from the guinea-pig. The drugs had similar activities as positive inotropic agents but RO363 was approximately 400 times less active than (−)−isoprenaline as a uterine relaxant. RO363 had intrinsic activities of 0.8 and 0.25 ((−)−isoprenaline = 1) in atrial and uterine preparations, respectively. 2 Apparent dissociation constants (KD values) determined from the ability of the agonists to displace (−)−[125I]-iodocyanopindolol ([125I]-CYP) bound to membranes prepared from both tissues were used as a measure of affinity. The [125I]-CYP binding sites possessed the characteristics of homogeneous populations of β1-adrenoceptors in atrial and β2-adrenoceptors in uterine membrane preparations. 3 The pKD values for (−)−isoprenaline were similar in the two tissues (left atria 6.4, uterus 6.0) whilst for RO363 the atrial value (7.8) was considerably greater than that for the uterus (6.0). The latter value is very similar to the pKB value determined from shifts in (−)−isoprenaline curves produced by RO363 in uterine preparations. 4 Graphical plots of the fraction of receptors occupied vs response were constructed. The relative efficacy of (−)−isoprenaline with respect to RO363 was calculated to be 25 in atrial and 2633 in uterine preparations. 5 The selective β1-adrenoceptor stimulant actions of RO363 are a reflection of both its greater affinity and efficacy for β1− as opposed to β2-adrenoceptor sites. The potent actions of (−)−isoprenaline in both tissues are largely dependent on efficacy.