DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain. (January 2016)

• Record Type: Journal Article
• Authors: Lopes, Alexandre H.; Brandolini, Laura; Aramini, Andrea; Bianchini, Gianluca; Silva, Rangel L.; Zaperlon, Ana C.; Verri, Waldiceu A.; Alves-Filho, José C.; Cunha, Fernando Q.; Teixeira, Mauro M.; Allegretti, Marcello; Cunha, Thiago M.
• Is Part Of: Pharmacological research. Volume 103(2016:Jan.)
• Page Start: 69
• Page End: 79
• Publication Date: 2016-01
• Subjects: CXCR1/2 chemokine (C-X-C motif) receptor 1/2 -- LPS lipopolysaccharide -- CFA complete freund's adjuvant -- CXCL8 chemokine (C-X-C motif) ligand 8 -- CNS central nervous system -- PMN polymorphonuclear cell family -- HBSS Hanks' balanced salt solution -- PGE2 prostaglandin E2 -- TRPV1 transient receptor potential cation channel subfamily V member 1 -- CGRP calcitonin gene related peptide -- ERK extracellular-signal-regulated kinases -- NMDA N-methyl-D-aspartate; Chemokines -- CXCR1/2 -- Inflammatory pain -- Neutrophil -- DF2755A -- Neutrophil chemotaxis -- Allosteric; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2015.11.005
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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 (3–30 mg/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.