Discovery of potent positive allosteric modulators of the α3β2 nicotinic acetylcholine receptor by a chemical space walk in ChEMBL

ACS Chem Neurosci. 2014 May 21;5(5):346-59. doi: 10.1021/cn4002297. Epub 2014 Mar 4.


While a plethora of ligands are known for the well studied α7 and α4β2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related α3β2 nAChR expressed in the central nervous system and at the neuromuscular junction. Starting with the public database ChEMBL organized in the chemical space of Molecular Quantum Numbers (MQN, a series of 42 integer value descriptors of molecular structure), a visual survey of nearest neighbors of the α7 nAChR partial agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) pointed to N-(2-halobenzyl)-3-aminoquinuclidines as possible nAChR modulators. This simple "chemical space walk" was performed using a web-browser available at . Electrophysiological recordings revealed that these ligands represent a new and to date most potent class of positive allosteric modulators (PAMs) of the α3β2 nAChR, which also exert significant effects in vivo. The present discovery highlights the value of surveying chemical space neighbors of known drugs within public databases to uncover new pharmacology.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Benzamides / pharmacology
  • Bridged Bicyclo Compounds / pharmacology
  • Databases, Chemical*
  • Dose-Response Relationship, Drug
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Models, Chemical
  • Nicotinic Agonists / pharmacology
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism*
  • Xenopus laevis


  • Benzamides
  • Bridged Bicyclo Compounds
  • Nicotinic Agonists
  • PNU-282987
  • Receptors, Nicotinic
  • nicotinic receptor alpha3beta2