A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes

Abstract

As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they may differ between parts of a tissue, for instance, atria vs. ventricles of the heart, and within a cell type, between cellular responses. The basal tone of endogenously expressed receptors is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.

Lipid Emulsion Enhances Vasoconstriction Induced by Dexmedetomidine in the Isolated Endothelium-Intact Aorta

“…Moreover, alpha-2 adrenoceptor inhibitor rauwolscine inhibited the DMT-induced eNOS phosphorylation and DMT-induced contraction ( Figure 3 C). In addition, rauwolscine-induced inhibition of eNOS (ser1177) phosphorylation ( Figure 7 ) seems to be due to inverse agonism [ 28 ]. Altogether, these results suggest that an increased stimulatory eNOS (Ser1177) phosphorylation and reduced inhibitory eNOS (Thr495) phosphorylation by DMT are mediated by the pathway involving caveolin-1 and Src kinase via alpha-2 adrenoceptor ( Figure 10 ) [ 16 , 25 , 26 , 27 ].…”

Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro

“…Nonetheless, despite similar surface receptor numbers, it is important to consider that α1D-ARs were expressed in Chem-1 cell lines, while α1A- and α1B-AR were in PC12 cells. Different expression systems might influence intracellular signaling from GPCRs, for example due to the different availability of intracellular signaling cascade components [ 27 ]. In fact, the Chemi-1 cells used to study α1D-ARs express high levels of G protein Gα15, which strongly couples expressed α1D-ARs to calcium signaling.…”

“…However, since it is currently unclear what the most relevant physiological form of surface-expressed α1D‑ARs (truncated, full length, heterodimer or another form) is in the CNS, a direct comparison between α1A- and α1B-AR vs. α1D-ARs IC 50 values would have to be done cautiously regardless of the model used. Future studies will hopefully be able to investigate multiple second messenger pathways simultaneously for all α1-AR subtypes in order to take into account biased signaling, and do it in multiple cellular systems, which might influence the antagonistic properties of ligands [ 27 ]. To make matters more complicated, different α1-AR subtypes can be co-expressed in the same cell type and are known to interact—in fact, α1B-AR and α1D-AR co-expression can rescue the membrane localization of the latter [ 36 ].…”

“…During preincubation with antidepressants, no agonist was present; therefore, the drugs might actually inhibit the intrinsic activity of the receptors. Inverse agonism has been demonstrated now to be common rather than an exception, including for α1-AR ligands [ 27 ]. Actually, α1A-AR has been shown to be internalized in an agonist-independent way, and this was linked with constitutive activity [ 38 ].…”

“…This supports the relevance of studies of α1-AR subtypes in antidepressant action, and prompts further investigation into the subject. More detailed investigations of specific drugs will be relevant, considering the complex regulation of intracellular signaling from α1-ARs and recent evidence that many compounds can act not only as full antagonists but also as partial or inverse agonists with potentially different short- and long-term effects on α1-AR signaling [ 27 ].…”