Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice

Abstract

Background and purposeThe κ receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although κ receptor agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain‐penetrant κ receptor ligands possessing biased agonism towards G protein signalling over β‐arrestin2 recruitment would produce robust antinociception with fewer associated liabilities.Experimental approachTwo new diphenethylamines with high κ receptor selectivity, HS665 and HS666, were assessed following i.c.v. administration in mouse assays of antinociception with the 55°C warm‐water tail withdrawal test, locomotor activity in the rotorod and conditioned place preference. The [35S]‐GTPγS binding and β‐arrestin2 recruitment in vitro assays were used to characterize biased agonism.Key resultsHS665 (κ receptor agonist) and HS666 (κ receptor partial agonist) demonstrated dose‐dependent antinociception after i.c.v. administration mediated by the κ receptor. These highly selective κ receptor ligands displayed varying biased signalling towards G protein coupling in vitro, consistent with a reduced liability profile, reflected by reduced sedation and absence of conditioned place aversion for HS666.Conclusions and implicationsHS665 and HS666 activate central κ receptors to produce potent antinociception, with HS666 displaying pharmacological characteristics of a κ receptor analgesic with reduced liability for aversive effects correlating with its low efficacy in the β‐arrestin2 signalling pathway. Our data provide further understanding of the contribution of central κ receptors in pain suppression, and the prospect of dissociating the antinociceptive effects of HS665 and HS666 from κ receptor‐mediated adverse effects.

Biased Opioid Ligands

“…The same study investigated the behavioral effects of HS665 and HS666 in vivo. Interestingly, neither of these agents significantly impacted motor performance at any time point and HS666 did not induce CPP/CPA (Conditioned Place Preference/Conditioned Place Aversion) while HS665 produced significant place aversion when administered 5 times their analgesic ED 90 [ 62 ]. It is not clear if HS666 did not show CPA because it was a partial agonist or if this was because of its G-protein bias.…”

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

“…More recently, triazole 1.1 was shown to induce dose-dependent, KOPr-mediated antinociception and to suppresses chloroquine phosphate-induced scratching responses in C57BL/6 mice without affecting ambulatory behaviors in mice (Brust et al, 2016). Furthermore, antinociception devoid of dysphoria promoted by a KOPr-selective, G-protein-biased agonist, was demonstrated also by other authors (Spetea et al, 2017). On the other hand, White and co-workers have reported that the G protein-biased KOPr agonist RB-64 induces antinociceptive effects in the hot-plate test without impairing rotarod performance or novelty-induced locomotion.…”

“…b-arrestin 2 recruitment at KOPr was investigated by using the DiscoveRxPathHunter ® eXpressb-arrestin2 assay (Eurofins-DiscoveRx, CA, USA) according to manufacturer's recommendations and previously published procedures (Zhou et al, 2013;Spetea et al, 2017). Briefly, U2OS cells provided with the kit and stably co-expressing the kappa receptor and the enzyme acceptor-tagged b-arrestin2 fusion protein were seeded in cell plating medium into 96-well plates (10,000 cells per well) and maintained for 48 h at 37°C.…”

A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

“…Drug candidates targeting this G protein-coupled receptor (GPCR) have been developed for neuropsychiatric disorders [ 2 ] and pain [ 3 , 4 ]. The concept of biased agonism [ 5 ] that distinguishes between GPCR activation and β-arrestin mediated signaling pathways has shown promise in the development of KOR-based analgesics with fewer side effects [ 6 , 7 ]. This is important for the development of new treatments for neuropathic pain (NP), which occurs in about 7% of the US population [ 8 ].…”