Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X7 antagonists

Derek W. Nelson*, Robert J. Gregg, Michael E. Kort, Arturo Perez-Medrano, Eric A. Voight, Ying Wang, George Grayson, Marian T. Namovic, Diana L. Donnelly-Roberts, Wende Niforatos, Prisca Honore, Michael F. Jarvis, Connie R. Faltynek, William A. Carroll

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

199 Scopus citations

Abstract

1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X? receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X7 cell lines using fluorometric imaging plate reader technology. Analogues were also assayed for their ability to inhibit IL-1β release and to inhibit P2X7-mediated pore formation in human THP-1 cells. Compound 15d was advanced to efficacy studies in a model of neuropathic pain where significant reversal of mechanical allodynia was observed at doses that did not affect motor coordination.

Original languageEnglish (US)
Pages (from-to)3659-3666
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number12
DOIs
StatePublished - Jun 15 2006

ASJC Scopus subject areas

  • Organic Chemistry

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