ArticleBritish journal of pharmacology2017
Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.
Article in British journal of pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 74 citations in OpenAlex.
- Rational design of a Kappa opioid receptor peptide agonist with attenuated β-arrestin signaling.Nature communications · 2026Article
- Mechanistic Insights into G Protein-Biased κ-Opioid Receptor Signaling Using Dual-Charged Naltrexamine Amides.Journal of medicinal chemistry · 2026Article
- Review
- KOR agonists for the treatment and/or prevention of opioid use disorder and cocaine use disorder.Pharmacology, biochemistry, and behavior · 2025Review
- Supraspinal kappa-opioid receptors: new therapeutic strategies for pain, pruritus, and negative emotions.Experimental brain research · 2025Article
- Effects of Biased Analogues of the Kappa Opioid Receptor Agonist, U50,488, in Preclinical Models of Pain and Side Effects.Molecules (Basel, Switzerland) · 2025Article
- Recommended Opioid Receptor Tool Compounds: ComparativeACS pharmacology & translational science · 2025Article
- Limitations and potential of κOR biased agonists for pain and itch management.Neuropharmacology · 2024Review
- Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.Nature communications · 2024Article
- Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening.Journal of medicinal chemistry · 2024Article
- Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.Nature communications · 2023Article
- IUPHAR themed review: Opioid efficacy, bias, and selectivity.Pharmacological research · 2023Review
- Tryptophan Substitution in CJ-15,208 (Pharmaceuticals (Basel, Switzerland) · 2023Article
- Cell-Penetrating Peptides as Valuable Tools for Nose-to-Brain Delivery of Biological Drugs.Cells · 2023Review
- Opioid signaling and design of analgesics.Progress in molecular biology and translational science · 2023Review
- Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects.Molecules (Basel, Switzerland) · 2023Review
- Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways.Molecules (Basel, Switzerland) · 2022Article
- Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics.International journal of molecular sciences · 2022Article
- The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys.Pharmacology, biochemistry, and behavior · 2022Article
- An analog of [d-Trp]CJ-15,208 exhibits kappa opioid receptor antagonism following oral administration and prevents stress-induced reinstatement of extinguished morphine conditioned place preference.Pharmacology, biochemistry, and behavior · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
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 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 [ 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 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.