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Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.
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- المؤلفون: Spetea, Mariana1,2 ; Eans, Shainnel O2,3; Ganno, Michelle L2; Lantero, Aquilino1; Mairegger, Michael1; Toll, Lawrence2; Schmidhammer, Helmut1; McLaughlin, Jay P2,3
- المصدر:
British Journal of Pharmacology. Aug2017, Vol. 174 Issue 15, p2444-2456. 13p.
- الموضوع:
- معلومة اضافية
- نبذة مختصرة :
Background and Purpose: The 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 Approach: Two 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 [35 S]-GTPγS binding and β-arrestin2 recruitment in vitro assays were used to characterize biased agonism.Key Results: HS665 (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 Implications: HS665 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. [ABSTRACT FROM AUTHOR]
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