Allosteric functional switch of neurokinin A-mediated signaling at the neurokinin NK2 receptor: structural exploration

J Med Chem. 2009 Oct 8;52(19):5999-6011. doi: 10.1021/jm900671k.


The neurokinin NK2 receptor is known to pre-exist in equilibrium between at least three states: resting-inactive, calcium-triggering, and cAMP-producing. Its endogeneous ligand, NKA, mainly induces the calcium response. Using a FRET-based assay, we have previously discovered an allosteric modulator of the NK2 receptor that has the unique ability to discriminate among the two signaling pathways: calcium-signaling is not affected while cAMP signaling is significantly decreased. A series of compounds have been prepared and studied in order to better understand the structural determinants of this allosteric functional switch of a GPCR. Most of them display the same allosteric profile, with smooth pharmacomodulation. One compound however exhibits significantly improved modulatory properties of NKA induced signaling when compared to the original modulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Animals
  • Calcium Signaling
  • Cyclic AMP
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Hydrocarbons, Aromatic / chemistry
  • Hydrocarbons, Aromatic / pharmacology
  • Ligands
  • Neurokinin A / chemistry*
  • Neurokinin A / metabolism
  • Protein Conformation / drug effects
  • Receptors, G-Protein-Coupled
  • Receptors, Neurokinin-2 / chemistry
  • Receptors, Neurokinin-2 / drug effects*
  • Receptors, Neurokinin-2 / metabolism
  • Signal Transduction / drug effects*


  • Hydrocarbons, Aromatic
  • Ligands
  • Receptors, G-Protein-Coupled
  • Receptors, Neurokinin-2
  • Neurokinin A
  • Cyclic AMP