Neurosteroid analogues. 14. Alternative ring system scaffolds: GABA modulatory and anesthetic actions of cyclopenta[b]phenanthrenes and cyclopenta[b]anthracenes

J Med Chem. 2008 Mar 13;51(5):1309-18. doi: 10.1021/jm701128r. Epub 2008 Feb 15.


Although the structural features of binding sites for neuroactive steroids on gamma-aminobutryic acid type A (GABA A) receptors are still largely unknown, structure-activity studies have established a pharmacophore for potent enhancement of GABA A receptor function by neuroactive steroids. This pharmacophore emphasizes the importance of the position and stereochemistry of hydrogen-bonding groups on the steroid. However, the importance of the steroid ring system in mediating hydrophobic interactions with the GABA A receptor is unclear. We have taken the cyclopenta[ b]phenanthrene (tetracyclic compounds with a nonlinear ring system different from that of steroids) and cyclopenta[ b]anthracene (tetracyclic molecules with a linear 6-6-6-5 carbocyclic ring system) ring systems and properly substituted them to satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids. We have found these cyclopenta[ b]phenanthrene and cyclopenta[ b]anthracene analogues to have potent activity at the GABA A receptor, rivaling that of the most potent steroid modulators. Single-channel analysis of electrophysiological data indicates that similarly substituted analogues in the different ring systems affect the kinetic components of macroscopic currents in different ways. Mutations to the hydrogen bonding amino acids at the putative steroid binding site (alpha1Q241L mutation and alpha1N407A/Y410F double mutation) produce similar effects on macroscopic current amplitude by the different ring system analogues suggesting that the different kinetic effects are explained by the precise interactions of each analogue with the same binding site(s).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anesthetics / chemical synthesis*
  • Anesthetics / chemistry
  • Anesthetics / pharmacology
  • Animals
  • Anthracenes / chemical synthesis*
  • Anthracenes / chemistry
  • Anthracenes / pharmacology
  • Binding Sites
  • Brain / metabolism
  • Cell Line
  • GABA Modulators / chemical synthesis*
  • GABA Modulators / chemistry
  • GABA Modulators / pharmacology
  • Humans
  • In Vitro Techniques
  • Larva
  • Models, Molecular
  • Mutation
  • Oocytes / drug effects
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Phenanthrenes / chemical synthesis*
  • Phenanthrenes / chemistry
  • Phenanthrenes / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / physiology*
  • Stereoisomerism
  • Steroids / pharmacology
  • Structure-Activity Relationship
  • Xenopus laevis


  • Anesthetics
  • Anthracenes
  • GABA Modulators
  • Phenanthrenes
  • Receptors, GABA-A
  • Steroids