DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain

Pharmacol Res. 2016 Jan;103:69-79. doi: 10.1016/j.phrs.2015.11.005. Epub 2015 Nov 28.

Abstract

The activation of CXCR1/2 has been implicated in the genesis of inflammatory and postoperative pain. Here, we investigated a novel orally acting allosteric inhibitor of CXCR1/2 (DF2755A) and evaluated its antinociceptive effect in several models of inflammatory and post-operatory pain. DF2755A was tested in vitro for efficacy in the chemotaxis assay, selectivity and toxicity. In vivo, C57Bl/6 mice were treated orally with DF2755A and the following experiments were performed: pharmacokinetic profile; inflammatory hyperalgesia models using electronic pressure meter test; neutrophil migration assay assessed by myeloperoxidase assay. DF2755A selectively inhibited neutrophil chemotaxis induced by CXCR1/2 ligands without effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF2755A on CXCL8-induced chemotaxis. DF2755A given orally was well absorbed (88.2%), and it was able to reduce, in a dose (3-30mg/kg)-dependent manner, inflammatory hyperalgesia induced by carrageenan, LPS and CXCL1/KC as well as neutrophil recruitment and IL-1β production. In addition, DF2755A was able to reduce post-incisional nociception. Therapeutic treatment with DF2755A reduced CFA-induced inflammatory hyperalgesia even when injected intrathecally. The present results indicate that DF2755A is a novel selective allosteric inhibitor of CXCR1/2 with a favorable oral pharmacokinetic profile. Furthermore, the results might suggest that DF2755A might be a candidate of a novel therapeutic option to control inflammatory and post-operative pain.

Keywords: Allosteric; CXCR1/2; Chemokines; DF2755A; Inflammatory pain; Neutrophil; Neutrophil chemotaxis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics / pharmacokinetics
  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Carrageenan
  • Cell Line, Tumor
  • Cell Movement
  • Cells, Cultured
  • Chemokine CXCL1 / metabolism
  • Dinoprostone / metabolism
  • Guinea Pigs
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy*
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / physiology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Pain, Postoperative / drug therapy*
  • Phenylacetates / pharmacokinetics
  • Phenylacetates / pharmacology
  • Phenylacetates / therapeutic use*
  • Physical Stimulation
  • Rabbits
  • Rats
  • Receptors, Interleukin-8A / antagonists & inhibitors
  • Receptors, Interleukin-8B / antagonists & inhibitors
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use*

Substances

  • Analgesics
  • Anti-Inflammatory Agents
  • Chemokine CXCL1
  • DF2755A
  • Interleukin-8
  • Phenylacetates
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Thiazoles
  • Carrageenan
  • Dinoprostone