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

BACKGROUND AND PURPOSE The. receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although. receptor agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain-penetrant. receptor ligands possessing biased agonism towards G protein signalling over beta-arrestin2 recruitment would produce robust antinociception with fewer associated liabilities. EXPERIMENTAL APPROACH Two new diphenethylamines with high kappa receptor selectivity, HS665 and HS666, were assessed following i.c.v. administration in mouse assays of antinociception with the 55 degrees C warm-water tail withdrawal test, locomotor activity in the rotorod and conditioned place preference. The [S-35]-GTP gamma S binding and beta-arrestin2 recruitment in vitro assays were used to characterize biased agonism. KEY RESULTS HS665 (kappa receptor agonist) and HS666 (kappa receptor partial agonist) demonstrated dose-dependent antinociception after i.c.v. administration mediated by the kappa receptor. These highly selective. 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 IMPLICATIONS HS665 and HS666 activate central. receptors to produce potent antinociception, with HS666 displaying pharmacological characteristics of a kappa receptor analgesic with reduced liability for aversive effects correlating with its low efficacy in the beta-arrestin2 signalling pathway. Our data provide further understanding of the contribution of central. receptors in pain suppression, and the prospect of dissociating the antinociceptive effects of HS665 and HS666 from kappa receptor-mediated adverse effects.