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.

Allosteric modulation of nicotinic acetylcholine receptors

“…In recent years, PAMs of α3-containing nAChRs have also been reported [96][97][98]. For example, the anthelmintic compounds levamisole and morantel potentiate acetylcholine response on α3β2 and α3β4.…”

Fluorescent Agonists of the α7 Nicotinic Acetylcholine Receptor Derived from 3‐Amino‐Quinuclidine

“…Sulfonamides ( R )‐ 8 and ( S )‐ 8 were obtained by acylation of 3‐amino‐quinuclidines with dansylsulfonyl chloride. Considering that an amide‐type linkage is not always necessary for an α 7 agonistic effect, we also performed direct palladium‐catalyzed Buchwald – Hartwig coupling of 3‐amino‐quinuclidine to the trifluoromethane sulfonates of umbelliferone and resorufin following two patent literature on derivatives of these fluorophores with other amines, to obtain the corresponding alklyated anilines ( R )‐ 9 /( S )‐ 9 and ( R )‐ 10 /( S )‐ 10 .…”

Functional Studies of Sodium Channels: From Target to Compound Identification

“…Although two-electrode voltage-clamp recording is amenable to automated assays in small cells, it is ideally suited for recording from Xenopus oocytes (Trumbull et al, 2003;Pehl et al, 2004;Leisgen et al, 2007;Kvist et al, 2011). Several commercially available solutions exist; we shall briefly describe how to take advantage of one of these automated recording platforms, the HiClamp from Multichannel Systems (Burgi et al, 2014;Chen et al, 2014). Design of the experiments requires proper reflection on both the objectives of the measurements as well as their analysis.…”