The selectivity of α‐adrenoceptor agonists for the human α1A, α1B, and α1D‐adrenoceptors

Abstract Highly selective drugs offer a way to minimize side‐effects. For agonist ligands, this could be through highly selective affinity or highly selective efficacy, but this requires careful measurements of intrinsic efficacy. The α1‐adrenoceptors are important clinical targets, and α1‐agonists are used to manage hypotension, sedation, attention deficit hypersensitivity disorder (ADHD), and nasal decongestion. With 100 years of drug development, there are many structurally different compounds with which to study agonist selectivity. This study examined 62 α‐agonists at the three human α1‐adrenoceptor (α1A, α1B, and α1D) stably expressed in CHO cells. Affinity was measured using whole‐cell 3H‐prazosin binding, while functional responses were measured for calcium mobilization, ERK1/2‐phosphorylation, and cAMP accumulation. Efficacy ratios were used to rank compounds in order of intrinsic efficacy. Adrenaline, noradrenaline, and phenylephrine were highly efficacious α1‐agonists at all three receptor subtypes. A61603 was the most selective agonist and its very high α1A‐selectivity was due to selective α1A‐affinity (>660‐fold). There was no evidence of Gq‐calcium versus ERK‐phosphorylation biased signaling at the α1A, α1B, or α1D‐adrenoceptors. There was little evidence for α1A calcium versus cAMP biased signaling, although there were suggestions of calcium versus cAMP bias the α1B‐adrenoceptor. Comparisons of the rank order of ligand intrinsic efficacy suggest little evidence for selective intrinsic efficacy between the compounds, with perhaps the exception of dobutamine which may have some α1D‐selective efficacy. There seems plenty of scope to develop affinity selective and intrinsic efficacy selective drugs for the α1‐adrenoceptors in future