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

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• 作者：Alexandre H. Lopes^a ; ^d ; Laura Brandolini^b ; ^d ; Andrea Aramini^b ; ^d ; Gianluca Bianchini^b ; ^d ; Rangel L. Silva^a ; ^d ; Ana C. Zaperlon^c ; ^d ; Waldiceu A. Verri Jr.^c ; ^d ; José ; C. Alves-Filho^a ; ^d ; Fernando Q. Cunha^a ; ^d ; Mauro M. Teixeira^c ; ^d ; Marcello Allegretti^b ; ^d ; ^{marcello.allegretti@dompe.it" class="auth_mail" title="E-mail the corresponding author} ; Thiago M. Cunha^a ; ^d ; ^{thicunha@fmrp.usp.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CXCR1/2 ; chemokine (C-X-C motif) receptor 1/2 ; LPS ; lipopolysaccharide ; CFA ; complete freund&rsquo ; s adjuvant ; CXCL8 ; chemokine (C-X-C motif) ligand 8 ; CNS ; central nervous system ; PMN ; polymorphonuclear cell family ; HBSS ; Hanks&rsquo ; 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
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：103
• 期：Complete
• 页码：69-79
• 全文大小：1655 K

文摘

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.