Affordable Access

deepdyve-link
Publisher Website

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.

Authors
  • Cao, Danni1, 2
  • Huang, Peng1
  • Chiu, Yi-Ting1
  • Chen, Chongguang1
  • Wang, Huiqun3
  • Li, Mengchu3
  • Zheng, Yi3
  • Ehlert, Frederick J4
  • Zhang, Yan3
  • Liu-Chen, Lee-Yuan1
  • 1 Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States. , (United States)
  • 2 Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. , (China)
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States. , (United States)
  • 4 Department of Pharmaceutical Sciences, Center of Health Sciences, University of California, Irvine, California 92697, United States. , (United States)
Type
Published Article
Journal
ACS Chemical Neuroscience
Publisher
American Chemical Society
Publication Date
Oct 07, 2020
Volume
11
Issue
19
Pages
3036–3050
Identifiers
DOI: 10.1021/acschemneuro.0c00407
PMID: 32897695
Source
Medline
Keywords
Language
English
License
Unknown

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 Y7.35 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.

Report this publication

Statistics

Seen <100 times