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Four D-amino acids and a spiro cap: a kappa agonist built to stay out of the brain.
Also known as: HSK21542 · peripheral kappa opioid receptor agonist
Part of the Neuropeptides & signaling cluster
Overview
Anrikefon (HSK21542) is a synthetic tetrapeptide of D-amino acids (D-Phe-D-Phe-D-Leu-D-Lys) capped with a 2-acetyl-2,7-diazaspiro[3.5]nonane group, C39H57N7O5, about 704 Da. It is a selective, peripherally restricted κ-opioid receptor agonist developed by Haisco for postoperative pain and uraemic itch. China's NMPA approved it in 2025 for mild-to-moderate pain after abdominal surgery; a 545-patient phase 3 trial in haemodialysis pruritus was published in the BMJ in 2025.
Source & context
Biological / chemical source: Synthetic D-Phe-D-Phe-D-Leu-D-Lys tetrapeptide capped with a 2-acetyl-2,7-diazaspiro[3.5]nonane group
Primary research or clinical context: Approved in China (NMPA, 2025) for mild-to-moderate pain after abdominal surgery; phase 3 completed in chronic kidney disease-associated pruritus
What anrikefon is
Anrikefon, developed by Haisco as HSK21542, is a novel and selective peripheral κ-opioid receptor (KOR) agonist with analgesic and anti-itch actions (IUPHAR record). Chemically it is a tetrapeptide of D-amino acids — D-phenylalanine, D-phenylalanine, D-leucine, D-lysine — whose C-terminal lysine is coupled to a 2-acetyl-2,7-diazaspiro[3.5]nonane group rather than a free carboxyl (PubChem record: C39H57N7O5, ≈704 Da). The D-configuration resists proteolysis, and the polar, charged structure limits passage across the blood–brain barrier, which is the design intent: kappa agonism in the periphery without the dysphoria and sedation that central KOR activation produces.
Mechanism: peripheral kappa agonism for pain and itch
κ-opioid receptors on peripheral sensory neurons and immune cells modulate both pain and itch signalling. A peripherally restricted agonist can therefore block pain and itch signals while avoiding the central effects of μ-opioids — dependence, gastrointestinal intolerance, respiratory depression — and the central κ effects of dysphoria (Wang et al., Expert Review of Clinical Pharmacology 2025; Azam et al., Journal of Pain & Palliative Care Pharmacotherapy 2026). Difelikefalin, also on this site, is the same pharmacological idea from another company and shares the D-amino-acid tetrapeptide architecture.
Clinical evidence: postoperative pain
A 2026 systematic review and meta-analysis identified three randomised controlled trials (n = 718) of intravenous anrikefon 1.0 µg/kg versus placebo for postoperative pain. Pooled analysis showed a significant improvement in the summed pain-intensity difference over 24 hours (mean difference −14.73; 95% CI −21.7 to −7.75; p < 0.0001) and reduced rescue-analgesic use within 12 hours (risk ratio 0.59; 95% CI 0.49–0.71), with a higher proportion of patients reaching a pain score of 3 or less at 12 hours (Azam et al., 2026). A trial in 387 abdominal-surgery patients compared anrikefon 1 µg/kg, tramadol 1 mg/kg and control, three doses every 8 hours, with subgroup analyses in elderly patients and those with mild-to-moderate kidney or liver injury (Xu et al., Journal of Anesthesia and Translational Medicine 2024). Population pharmacokinetics from six trials fit a three-compartment model with linear elimination and weight-based allometric scaling (Wang et al., 2025).
| Outcome | Result |
|---|---|
| SPID 0–24 h (mean difference) | −14.73 (95% CI −21.7 to −7.75) |
| Rescue analgesic use within 12 h | RR 0.59 (95% CI 0.49–0.71) |
| NRS ≤ 3 at 12 h | Higher with anrikefon |
Clinical evidence: uraemic pruritus
A multicentre, double-blind, randomised, placebo-controlled phase 3 trial at 50 centres in China (June 2022 to June 2024) screened 652 haemodialysis patients with moderate-to-severe chronic kidney disease-associated pruritus and randomised 545 to intravenous anrikefon 0.3 µg/kg or placebo three times weekly for 12 weeks, followed by an optional 40-week open-label extension. The primary endpoint was the proportion achieving at least a 4-point reduction in weekly mean worst-itch numerical rating scale from baseline to week 12; secondary outcomes included a 3-point reduction and itch-related quality of life (Skindex-10, 5-D itch). Of the randomised patients, 243/275 (88%) on anrikefon and 254/270 (94%) on placebo completed the double-blind period, and 443 entered the extension (Liu et al., BMJ 2025). The BMJ published an accompanying patient-and-clinician commentary (Rayner & van Wyk, BMJ 2025).
Regulatory status as of September 2026
China's NMPA granted first approval in 2025 for the treatment of mild-to-moderate pain after abdominal surgery (IUPHAR clinical-use record). Anrikefon is not approved in the United States, Canada or the European Union. ClinicalTrials.gov lists ten studies, including phase 4 trials of multimodal postoperative analgesia and patient-controlled intravenous analgesia after laparoscopic surgery, a phase 4 comparison against nalfurafine for sleep quality in haemodialysis patients with CKD-associated pruritus, and further phase 2 postoperative studies. It is a hospital prescription medicine; this profile is educational and not clinical guidance.
How it relates to other peptides on this site
Difelikefalin is the direct comparator: another D-amino-acid tetrapeptide peripheral κ-agonist, approved in the US and EU for haemodialysis-associated pruritus. Dynorphin is the endogenous κ-opioid peptide whose receptor both drugs target. The endomorphins and other opioid peptides on this site act at μ receptors and illustrate why peripheral restriction matters for the kappa class.
Sequence
One-letter sequence commonly cited for Anrikefon (educational; isoforms and modifications may differ):
FFLK
Residues plotted ~100° apart around an α-helix — clustering of one color reveals an amphipathic face.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Tetrapeptide of D-amino acids with a non-peptidic C-terminal cap
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- IUPHAR/BPS source snapshot · 2026-10-01
- PubChem molecular record · 2026-10-01
D-Phe-D-Phe-D-Leu-D-Lys-(2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)
- Molecular formula
- C39H57N7O5
- Average reference mass
- ≈ 703.9
- Receptors
- κ-opioid receptor (KOR), peripherally restricted; selective over μ and δ
- Backbone
- Tetrapeptide of D-amino acids with a non-peptidic C-terminal cap
- Status
- Approved in China (NMPA, 2025) for postoperative pain; phase 3 in CKD-associated pruritus; not approved in the US, Canada or EU as of September 2026
Unk= 2-acetyl-2,7-diazaspiro[3.5]nonane
- PubChem CID: 137433038
- IUPHAR ligand: 14403
- ChEMBL: CHEMBL5095089
- DrugBank: DB21529
- CAS RN: 2269511-95-5
- UNII: 22SCY98BXV
Chemistry values: curated profile, PubChem, IUPHAR/BPS Guide to Pharmacology · fetched 2026-10-01.
Clinical development snapshot
ClinicalTrials.gov lists 13 registered studies with “Anrikefon” as an intervention (snapshot 2026-10-01). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT07330063 | Efficacy and Safety of Anrikefon Injection for the Treatment of Postoperative Pain in Patients Undergoing Tota | Phase 2 | recruiting | 2026-09-22 |
| NCT07825142 | A Randomized, Double-Blind, Placebo-Controlled Trial of Anrikefon for Postoperative Analgesia After Percutaneo | Phase 4 | not yet recruiting | 2026-09-17 |
| NCT07826806 | Efficacy and Safety of Anrikefon Injection for the Treatment of Postoperative Pain in Patients Undergoing Lapa | Phase 2 | not yet recruiting | 2026-09-17 |
| NCT07810413 | Anrikefon Injection for Postoperative Analgesia in Thoracoscopic Lung Surgery: A Randomized, Double-Blind, Act | Not applicable | not yet recruiting | 2026-09-09 |
| NCT07801183 | Efficacy and Safety of Anrikefon Injection for Multimodal Postoperative Analgesia in Patients Undergoing Lapar | Phase 4 | not yet recruiting | 2026-09-03 |
| NCT07380113 | Anrikefon vs Nalfurafine for Sleep Quality in Hemodialysis Patients With CKD-aP | Phase 4 | recruiting | 2026-08-25 |
Anrikefon — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Tetrapeptide of D-amino acids with a non-peptidic C-terminal capAverage reference mass: 703.9 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- Trials3 registered studies added on ClinicalTrials.gov (now 13).
- IdentifiersCross-linked to IUPHAR ligand 14403 and PubChem CID 137433038.
- TrialsClinicalTrials.gov snapshot added: 10 registered studies, highest phase 4.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Anrikefon
What is Anrikefon?+
Anrikefon (HSK21542) is a synthetic tetrapeptide of D-amino acids (D-Phe-D-Phe-D-Leu-D-Lys) capped with a 2-acetyl-2,7-diazaspiro[3.5]nonane group, C39H57N7O5, about 704 Da. It is a selective, peripherally restricted κ-opioid receptor agonist developed by Haisco for postoperative pain and uraemic itch. China's NMPA approved it in 2025 for mild-to-moderate pain after abdominal surgery; a 545-patient phase 3 trial in haemodialysis pruritus was published in the BMJ in 2025.
What Canadian product status is recorded for Anrikefon?+
Canadian product status for Anrikefon has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Anrikefon?+
Anrikefon is commonly described as approximately 4 amino acids (Peripherally restricted κ-opioid receptor agonist (D-amino-acid tetrapeptide)).
What is anrikefon?+
A synthetic D-amino-acid tetrapeptide (HSK21542) that selectively activates peripheral κ-opioid receptors, developed by Haisco for postoperative pain and uraemic itch.
Is anrikefon approved?+
In China, yes — NMPA approval in 2025 for mild-to-moderate pain after abdominal surgery. Not approved in the US, Canada or EU as of September 2026.
How does anrikefon differ from morphine-type opioids?+
It targets κ rather than μ receptors and is designed not to enter the brain, avoiding dependence, respiratory depression and central side effects; its evidence shows reduced rescue-analgesic use after surgery.
What did the pruritus trial show?+
A 545-patient phase 3 trial in haemodialysis patients tested 0.3 µg/kg three times weekly for 12 weeks with a 4-point itch-score reduction as the primary endpoint; 88% of anrikefon patients completed the blinded period.
How does anrikefon compare with difelikefalin?+
Both are peripherally restricted κ-agonist tetrapeptides of D-amino acids; difelikefalin is approved in Western markets for dialysis itch, anrikefon in China for postoperative pain.
Related peptides
References & further reading
- 1.Liu BC et al. (2025). Efficacy and safety of anrikefon in patients with pruritus undergoing haemodialysis: multicentre, double blind, randomised placebo controlled phase 3 trial. BMJ
- 2.Azam MT et al. (2026). Efficacy and Safety of Anrikefon (HSK21542) for Postoperative Pain. A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Pain Palliat Care Pharmacother
- 3.Wang K et al. (2025). Population pharmacokinetic modeling and exposure-response analysis of anrikefon: insights and implications in clinical analgesia. Expert Rev Clin Pharmacol
- 4.Xu Y et al. (2024). Efficacy and safety of anrikefon injection for postoperative analgesia in specific patient groups (elderly, liver damage, renal damage) after abdominal surgery. J Anesth Transl Med
- 5.Rayner H, van Wyk V (2025). Anrikefon for itching related to chronic kidney disease. BMJ
- 6.PubChem — compound summary for Anrikefon (CID 137433038)