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

Abstract

1(-)-Isoprenaline and the selective P1-adrenoceptor agonist R0363 were tested for their inotropic effects in left atrial (1i,) 3 The pKD values for (-)-isoprenaline were similar in the two tissues (left atria 6.4, uterus 6.0) whilst for R0363 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 R0363 in uterine preparations. 4 Graphical plots of the fraction of receptors occupied vs response were constructed. The relative efficacy of (-)-isoprenaline with respect to R0363 was calculated to be 25 in atrial and 2633 in uterine preparations.5 The selective Pf-adrenoceptor stimulant actions of R0363 are a reflection of both its greater affinity and efficacy for Pl-as opposed to P2-adrenoceptor sites. The potent actions of (-)-isoprenaline in both tissues are largely dependent on efficacy.

β1-Selective Agonist (−)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(−)-RO363] Differentially Interacts with Key Amino Acids Responsible for β1-Selective Binding in Resting and Active States

“…1). The affinity of (Ϫ)-RO363 for ␤ 1 -adrenergic receptor is about 100-and 3000-fold higher than for ␤ 2 -and ␤ 3 -adrenergic receptors, respectively (McPherson et al, 1984;Molenaar et al, 1997). Therefore, we used (Ϫ)-RO363 as a tool to examine the contribution of key amino acids responsible for the ␤ 1 -selective binding to the binding in the resting and an active states.…”

The in vitro pharmacology of xamoterol (ICI 118,587)

“…24 h) were prepared in a Krebs phosphate buffer (pH 7.4) as previously described (McPherson et al, 1984 (McPherson, 1983a;b) which performed preliminary Hofstee analysis and created a file for the second programme, LIGAND (Munson & Rodbard, 1980). The latter was used to obtain final parameter estimates.…”

Activation of β2- and β3-Adrenergic Receptors Increases Brain Tryptophan

“…The receptor subtypes differ primarily in their location: ␤ 1 -adrenoceptors predominate in the heart, cerebral cortex, and kidney (Minneman et al, 1979;McPherson et al, 1984;Engel et al, 1985). The major ␤-adrenergic subtype in the lungs, cerebellum, uterus, skel-…”

“…The receptor subtypes differ primarily in their location: ␤ 1 -adrenoceptors predominate in the heart, cerebral cortex, and kidney (Minneman et al, 1979;McPherson et al, 1984;Engel et al, 1985). The major ␤-adrenergic subtype in the lungs, cerebellum, uterus, skel-etal muscle, and blood vessels is the ␤ 2 -adrenoceptor (Minneman et al, 1979;Carswell and Nahorski, 1983;McPherson et al, 1984;O'Donnell and Wanstall, 1985;Jensen et al, 1995). The ␤ 3 -adrenoceptor is expressed at high levels in brown and white adipose tissue, but has also been detected in brain, stomach, and gall bladder (Guillaume et al, 1994;Summers et al, 1995;Evans et al, 1996).…”