Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human β₂ Adrenoceptor

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

“…Some reports have described “superagonists” as compounds that have efficacy in the assay greater than that of the natural full agonist for membrane receptors, such as nicotinic acetylcholine receptors or adrenergic β 2 -receptors. − Therefore, the above data showed that compound 2 possesses agonistic ability superior to natural agonist OT, which indicated that it is a superagonist. This is the first example of a superagonist for OTR.…”

Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long‐term impairment of the GIP system

“…The longer a certain drug occupies a receptor, the more profound effect is obtained, thus a higher efficacy may be reached . This has for instance been shown for the β 2 ‐adrenoceptor agonist, C26, having a longer residence time and higher potency and efficacy in several distinct signalling pathways compared with the endogenous agonist adrenaline . Furthermore, it has been shown for three adenosine A 1 receptor (A 1 R) agonists, all having similar affinity, but different binding kinetics, where the agonist (LUF6941) with the longest residence time had the greatest anti‐lipolytic effect in rat adipocytes .…”

Pharmacology and Therapeutics of Bronchodilators Revisited

“…By accessing effectors from subcellular compartments, internalized receptors can form active ternary complexes that also contribute to cellular signaling. An incessant signaling from internalized compartments contributes to the overall extent of intracellular signaling as well as to the duration of cellular responses and can cause signal distortion by directing receptors toward alternative pathways/compartments or degradation (Rosethorne et al, 2016), socalled biased agonism.…”

“…Furthermore, the disclosure of the marine natural product S1319 as a b 2 -AR agonist with equivalent activity to formoterol, due to the presence of the 4-hydroxybenzothiazolone as a phenol-containing bicyclic catechol mimetic, has led to the exploration of a 4-hydroxybenzothiazolone series of b 2 -AR agonists (Beattie et al, 2010). 7-[(R)-2-((1R,2R)-2benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone (C26) was originally identified as a high-affinity b 2 -AR agonist with a predicted long duration of action and this compound exhibited greater intrinsic activity than endogenous adrenaline in producing increases in cAMP and moreover it recruited b-arrestin-2, and internalized the b 2 -AR slower than isoprenaline and adrenaline (Rosethorne et al, 2016). Compound C26 caused b-arrestin-2 recruitment with levels that increased up to 4 hours, when the intrinsic activity was 126% 6 3.52% of the maximal response to isoprenaline.…”

“…Compound C26 also displayed very slow receptor kinetics, with a receptor residence half-life of 32.7 minutes at 37°C, which is the slowest dissociation rate detected for any b 2 -AR agonist examined to date. Because of these characteristics, it was proposed that compound C26 acts as a superagonist (Rosethorne et al, 2016). Superagonists at GPCRs may have relevance in therapy, specifically compensating for the reduction in the effectiveness of drugs as a result of desensitization that can sometimes occur after continuous therapy with some agonists (Schrage et al, 2016).…”