Discovery of potent positive allosteric modulators of the ?3?2 nicotinic acetylcholine receptor by a chemical space walk in chembl

Abstract

While a plethora of ligands are known for the well studied ?7 and ?4?2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related ?3?2 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 ?7 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 ?3?2 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. � 2014 American Chemical Society.