GABA(C) receptors as drug targets

Curr Drug Targets CNS Neurol Disord. 2003 Aug;2(4):260-8. doi: 10.2174/1568007033482805.

Abstract

GABA(C) receptors are the least studied of the three major classes of GABA receptors. The physiological roles of GABA(C) receptors are still being unravelled and the pharmacology of these receptors is being developed. A range of agents has been described that act on GABA(C) receptors with varying degrees of specificity as agonists, partial agonists, antagonists and allosteric modulators. Pharmacological differences are known to exist between subtypes of cloned GABA(C) receptors that have been cloned from mammalian sources. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and gastrointestinal tract. Given the lower abundance and less widespread distribution of GABA(C) receptors in the CNS compared to GABA(A) receptors, GABA(C) receptors may be a more selective drug target than GABA(A) receptors. The major indications for drugs acting on GABA(C) receptors are in the treatment of visual, sleep and cognitive disorders. The most promising leads are THIP, a GABA(C) receptor antagonist in addition to its well known activity as a GABA(A) receptor partial agonist, which is being evaluated for sleep therapy, and CGP36742, an orally active GABA(B) and GABA(C) receptor antagonist, which enhances cognition. Analogues of THIP and CGP36742, such as aza-THIP, that are selective for GABA(C) receptors are being developed. TPMPA and related compounds such as P4MPA, PPA and SEPI are also important leads for the development of systemically active selective GABA(C) receptor antagonists.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation / physiology
  • Animals
  • Brain Chemistry / drug effects
  • Central Nervous System / drug effects
  • Central Nervous System / physiology
  • Chloride Channels / drug effects*
  • Drug Design
  • GABA Agonists / chemistry
  • GABA Agonists / pharmacology*
  • GABA Antagonists / chemistry
  • GABA Antagonists / pharmacology*
  • Humans
  • Hydroxybutyrates / metabolism*
  • Ion Channel Gating / physiology
  • Mice
  • Mice, Knockout
  • Receptors, GABA / chemistry
  • Receptors, GABA / classification
  • Receptors, GABA / drug effects*
  • Receptors, GABA / metabolism
  • Tissue Distribution

Substances

  • Chloride Channels
  • GABA Agonists
  • GABA Antagonists
  • GABA-C receptor
  • Hydroxybutyrates
  • Receptors, GABA
  • 4-hydroxybutyric acid