Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae

Bioorg Med Chem. 2010 Apr 15;18(8):2912-9. doi: 10.1016/j.bmc.2010.03.002. Epub 2010 Mar 6.

Abstract

Screening an extract library of >2500 southern Australian and Antarctic marine invertebrates and algae for modulators of glycine receptor (GlyR) chloride channels identified three Irciniidae sponges that yielded new examples of a rare class of glycinyl lactam sesterterpene, ircinialactam A, 8-hydroxyircinialactam A, 8-hydroxyircinialactam B, ircinialactam C, ent-ircinialactam C and ircinialactam D. Structure-activity relationship (SAR) investigations revealed a new pharmacophore with potent and subunit selective modulatory properties against alpha1 and alpha3 GlyR isoforms. Such GlyR modulators have potential application as pharmacological tools, and as leads for the development of GlyR targeting therapeutics to treat chronic inflammatory pain, epilepsy, spasticity and hyperekplexia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Australia
  • Cell Line
  • Humans
  • Indole Alkaloids / chemistry*
  • Indole Alkaloids / isolation & purification
  • Indole Alkaloids / pharmacology
  • Lactams / chemistry*
  • Lactams / isolation & purification
  • Lactams / pharmacology
  • Porifera / metabolism
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Receptors, Glycine / chemistry
  • Receptors, Glycine / metabolism*
  • Structure-Activity Relationship

Substances

  • 8-hydroxyircinialactam A
  • Indole Alkaloids
  • Lactams
  • Protein Isoforms
  • Receptors, Glycine
  • ircinialactam A
  • ircinialactam C