title: Discovery of potent positive allosteric modulators of the α3β2 nicotinic acetylcholine receptor by a chemical space walk in ChEMBL.
abstract: 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 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 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.
authors.affiliation: Department of Chemistry and Biochemistry, NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Justus J
authors.initials: JJ
authors.lastname: Bürgi
authors.forename: Mahendra
authors.initials: M
authors.lastname: Awale
authors.forename: Silvan D
authors.initials: SD
authors.lastname: Boss
authors.forename: Tifany
authors.initials: T
authors.lastname: Schaer
authors.forename: Fabrice
authors.initials: F
authors.lastname: Marger
authors.forename: Juan M
authors.initials: JM
authors.lastname: Viveros-Paredes
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D062126:Databases, Chemical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008956:Models, Chemical; D018722:Nicotinic Agonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D018722:Nicotinic Agonists; C498513:PNU-282987; D011978:Receptors, Nicotinic; C419362:nicotinic receptor alpha3beta2