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.

Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors

“…Or does DA induce a physical interaction between the bound DR and 1-AR, which then drives downstream Ca 2+ mobilization? While radioligand binding studies indicate that non-specific interaction of DA with 1-AR only occurs at sub-millimolar concentrations (Proudman and Baker, 2021;Steinberg and Bilezikian, 1982) (much higher than those used in the present experiments), D1 and 1AR colocalize on PFC dendrites and have been suggested to undergo co-trafficking (Mitrano et al, 2014). In addition, mounting evidence from co-immunoprecipitation, BRET/FRET sensors and proximity-ligation assays support the idea that DRs can form functional heteromeric complexes with ARs and other class A GPCRs (Azdad et al, 2009;Bonaventura et al, 2014;González et al, 2012;Kolasa et al, 2018;Lee et al, 2004;Moreno et al, 2014;Navarro et al, 2018;Pelassa et al, 2019;Rebois et al, 2012;Trifilieff et al, 2011;Valle-León et al, 2021;Zhu et al, 2020), although evidence against the existence of DR heteromers in vivo also exists (Frederick et al, 2015).…”

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats

“…The SM-MHC/NM-MHC ratio was not different between the two experimental groups (Figure 5f). The mRNA levels of α 1aadrenoceptor, a subtype that is preferentially activated by methoxamine [33], were not different in arterial samples of L-NAME and control pups (Figure 5g).…”

“…Indeed, the augmented sensitivity of chronically denervated arteries to adrenoceptor agonists was shown in several studies [14,[48][49][50]. Commonly, post-denervation hypersensitivity occurs without changes in total density or the affinity of post-junctional α 1A -adrenoceptors [51,52], which have the highest affinity to methoxamine compared to B and D subtypes [33]. Presumably, the same took place in twoweek-old offspring of L-NAME-treated females, because the content of α 1A -adrenoceptor mRNA in arterial tissue was not changed by maternal L-NAME treatment.…”

The signaling and selectivity of α‐adrenoceptor agonists for the human α2A, α2B and α2C‐adrenoceptors and comparison with human α1 and β‐adrenoceptors

“…The affinity of the agonists was assessed using the whole cell binding and is identical to that used to determine the affinity of agonists at the α1‐adrenoceptors 39 and β‐adrenoceptors. 38 Cells were grown to confluence in white‐sided 96‐well plates.…”

“…This study measured the Gi and Gs‐coupled agonist responses and binding affinity of a wide range of α‐agonists in CHO cells expressing the human α2A, α2B or α2C‐adrenoceptor and investigated, then uncovered, the reason why some agonists induce Gs‐stimulation whilst others do not. Furthermore, as these measurements were determined using exactly the same technique in human β1 and β2‐adrenoceptors and α1‐adrenoceptors , 39 this study provides a data set of the affinity, intrinsic efficacy and selectivity of ligands across the 8 most commonly targeted human adrenoceptors, measured under identical conditions.…”