Comparison of Pharmacological Properties between the Kappa Opioid Receptor Agonist Nalfurafine and 42B, Its 3-Dehydroxy Analogue: Disconnect between in Vitro Agonist Bias and in Vivo Pharmacological Effects

Abstract

Nalfurafine, a moderately selective kappa opioid receptor (KOR) agonist, is used in Japan for treatment of itch without causing dysphoria or psychotomimesis. Here we characterized the pharmacology of compound 42B, a 3-dehydroxy analogue of nalfurafine and compared with that of nalfurafine. Nalfurafine and 42B acted as full KOR agonists and partial μ opioid receptor (MOR) agonists, but 42B showed much lower potency for both receptors and lower KOR/MOR selectivity, different from previous reports. Molecular modeling revealed that water-mediated hydrogen-bond formation between 3-OH of nalfurafine and KOR accounted for its higher KOR potency than 42B. The higher potency of both at KOR over MOR may be due to hydrogen-bond formation between nonconserved Y 7.35 of KOR and their carbonyl groups. Both showed modest G protein signaling biases. In mice, like nalfurafine, 42B produced antinociceptive and antiscratch effects and did not cause conditioned place aversion (CPA) in the effective dose ranges. Unlike nalfurafine, 42B caused motor incoordination and hypolocomotion. As both agonists showed G protein biases, yet produced different effects on locomotor activity and motor incoordination, the findings and those in the literature suggest caution in correlating in vitro biochemical data with in vivo behavior effects. The factors contributing to the disconnect, including pharmacodynamic and pharmacokinetic issues, are discussed. In addition, our results suggest that among the KOR-induced adverse behaviors, CPA can be separated from motor incoordination and hypolocomotion.

Agonist-Promoted Phosphorylation and Internalization of the Kappa Opioid Receptor in Mouse Brains: Lack of Connection With Conditioned Place Aversion

“…Nalfurafine is a moderately selective KOR agonist and has 4,5-epoxymorphinan structure ( Seki et al, 1999 ). 42b is 3-deoxy nalfurafine and has moderate selectivity for the KOR ( Nagase and Fujii, 2013 ; Cao et al, 2020 ).…”

“…We previously performed in vitro and in vivo pharmacological characterization of these compounds ( Wang et al, 2008 ; Liu et al, 2019 ; Cao et al, 2020 ). EC 50 values and maximal effects of the four KOR agonists in stimulating KOR-mediated [ 35 S]GTPγS binding are shown in Supplementary Table S1 .…”

“…EC 50 values and maximal effects of the four KOR agonists in stimulating KOR-mediated [ 35 S]GTPγS binding are shown in Supplementary Table S1 . In addition, EC 50 values and maximal effects of nalfurafine and 42b in stimulating [ 35 S]GTPγS binding mediated by mu, delta, and nociceptin/orphanin FQ receptors (MOR, DOR, and NOR, respectively) are included in Supplementary Table S1 ( Wang et al, 2008 ; Liu et al, 2019 ; Cao et al, 2020 ). The four agonists dose-dependently produced analgesic effects in the formalin test and inhibition of scratching induced by compound 48/80 ( Supplementary Figures S1 and S2 ) ( Liu et al, 2019 ; Cao et al, 2020 ).…”

“…In addition, EC 50 values and maximal effects of nalfurafine and 42b in stimulating [ 35 S]GTPγS binding mediated by mu, delta, and nociceptin/orphanin FQ receptors (MOR, DOR, and NOR, respectively) are included in Supplementary Table S1 ( Wang et al, 2008 ; Liu et al, 2019 ; Cao et al, 2020 ). The four agonists dose-dependently produced analgesic effects in the formalin test and inhibition of scratching induced by compound 48/80 ( Supplementary Figures S1 and S2 ) ( Liu et al, 2019 ; Cao et al, 2020 ). We have also demonstrated that s.c. administration of U50,488H (0.25–10 mg/kg) and MOM-SalB (0.01–0.3 mg/kg) caused CPA, whereas nalfurafine (2.5–20 μg/kg) and 42B (1–5 mg/kg) did not ( Liu et al, 2019 ; Cao et al, 2020 ) ( Supplementary Figure S3 ).…”

“…The four agonists dose-dependently produced analgesic effects in the formalin test and inhibition of scratching induced by compound 48/80 ( Supplementary Figures S1 and S2 ) ( Liu et al, 2019 ; Cao et al, 2020 ). We have also demonstrated that s.c. administration of U50,488H (0.25–10 mg/kg) and MOM-SalB (0.01–0.3 mg/kg) caused CPA, whereas nalfurafine (2.5–20 μg/kg) and 42B (1–5 mg/kg) did not ( Liu et al, 2019 ; Cao et al, 2020 ) ( Supplementary Figure S3 ). In addition, U50,488H (5 mg/kg) and 42B (5 mg/kg), but not nalfurafine (20 μg/kg), induced hypolocomotion ( Liu et al, 2019 ; Cao et al, 2020 ) ( Supplementary Figure S4 ).…”