Title : Discovery of potent positive allosteric modulators of the alpha3beta2 nicotinic acetylcholine receptor by a chemical space walk in ChEMBL - Burgi_2014_ACS.Chem.Neurosci_5_346 |
Author(s) : Burgi JJ , Awale M , Boss SD , Schaer T , Marger F , Viveros-Paredes JM , Bertrand S , Gertsch J , Bertrand D , Reymond JL |
Ref : ACS Chem Neurosci , 5 :346 , 2014 |
Abstract :
While a plethora of ligands are known for the well studied alpha7 and alpha4beta2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related alpha3beta2 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 alpha7 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 www.gdb.unibe.ch . Electrophysiological recordings revealed that these ligands represent a new and to date most potent class of positive allosteric modulators (PAMs) of the alpha3beta2 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. |
PubMedSearch : Burgi_2014_ACS.Chem.Neurosci_5_346 |
PubMedID: 24593915 |
Burgi JJ, Awale M, Boss SD, Schaer T, Marger F, Viveros-Paredes JM, Bertrand S, Gertsch J, Bertrand D, Reymond JL (2014)
Discovery of potent positive allosteric modulators of the alpha3beta2 nicotinic acetylcholine receptor by a chemical space walk in ChEMBL
ACS Chem Neurosci
5 :346
Burgi JJ, Awale M, Boss SD, Schaer T, Marger F, Viveros-Paredes JM, Bertrand S, Gertsch J, Bertrand D, Reymond JL (2014)
ACS Chem Neurosci
5 :346