On the nature of partial agonism in the nicotinic receptor superfamily

Nature. 2008 Aug 7;454(7205):722-7. doi: 10.1038/nature07139. Epub 2008 Jul 16.


Partial agonists are ligands that bind to receptors but produce only a small maximum response even at concentrations where all receptors are occupied. In the case of ligand-activated ion channels, it has been supposed since 1957 that partial agonists evoke a small response because they are inefficient at eliciting the change of conformation between shut and open states of the channel. We have investigated partial agonists for two members of the nicotinic superfamily-the muscle nicotinic acetylcholine receptor and the glycine receptor-and find that the open-shut reaction is similar for both full and partial agonists, but the response to partial agonists is limited by an earlier conformation change ('flipping') that takes place while the channel is still shut. This has implications for the interpretation of structural studies, and in the future, for the design of partial agonists for therapeutic use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Drug Partial Agonism*
  • Glycine / pharmacology
  • Humans
  • Membrane Potentials / drug effects
  • Muscles / metabolism
  • Nicotinic Agonists / pharmacology*
  • Protein Conformation
  • Protein Subunits / agonists
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Quaternary Ammonium Compounds / pharmacology
  • Rats
  • Receptors, Glycine / agonists
  • Receptors, Glycine / chemistry
  • Receptors, Glycine / genetics
  • Receptors, Glycine / metabolism
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship
  • Taurine / pharmacology


  • Nicotinic Agonists
  • Protein Subunits
  • Quaternary Ammonium Compounds
  • Receptors, Glycine
  • Receptors, Nicotinic
  • Taurine
  • tetramethylammonium
  • Glycine