Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists

Bioorg Med Chem Lett. 2009 Feb 1;19(3):954-8. doi: 10.1016/j.bmcl.2008.11.088. Epub 2008 Nov 27.

Abstract

Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X(7) antagonists. To assess their structure-activity relationships, these compounds were modified at their R(1) and R(2) groups and assayed for their ability to inhibit the 2'(3')-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X(7) receptor, and their ability to inhibit BzATP-induced IL-1beta release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R(1) position, and especially compound 19h, with the 2-NO(2)-4,5-dimethoxy-benzyl group at the R(2) position, had potent inhibitory efficacy as P2X(7) antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / chemistry
  • Alkaloids / chemistry
  • Berberine Alkaloids / pharmacology
  • Cell Differentiation
  • Cell Line
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Ethidium / chemistry
  • Ethidium / pharmacokinetics
  • Humans
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / chemistry
  • Models, Chemical
  • Purinergic P2 Receptor Antagonists*
  • Quinolizines / chemical synthesis*
  • Receptors, Purinergic P2X7
  • Structure-Activity Relationship

Substances

  • 5,6-dihydrodibenzo(a,g)quinolizinium
  • Alkaloids
  • Berberine Alkaloids
  • Interleukin-1beta
  • Lipopolysaccharides
  • P2RX7 protein, human
  • Purinergic P2 Receptor Antagonists
  • Quinolizines
  • Receptors, Purinergic P2X7
  • protoberberine
  • KN 62
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Ethidium