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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.

SUBMITTER: Burgi JJ

PROVIDER: S-EPMC4031035 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Bürgi Justus J JJ Awale Mahendra M Boss Silvan D SD Schaer Tifany T Marger Fabrice F Viveros-Paredes Juan M JM Bertrand Sonia S Gertsch Jürg J Bertrand Daniel D Reymond Jean-Louis JL

ACS chemical neuroscience 20140304 5

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-azabicy ...[more]

PMID: 24593915

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Project description:Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding to an extracellular site located at the interface of two adjacent subunits. In contrast, recent studies have provided evidence that positive allosteric modulators (PAMs) such as TQS (4-(naphthalen-2-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and allosteric agonists such as 4BP-TQS (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) interact at an intrasubunit transmembrane site. Here, we describe the synthesis and pharmacological characterization of a series of chemically related allosteric modulators of the α7 nAChR. Minimal changes in the chemical structure of these compounds have been found to exert profound effects on their pharmacological properties. For example, compounds containing a bromine atom at either the ortho or meta position on the phenyl ring, such as 2BP-TQS (4-(2-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) and 3BP-TQS (4-(3-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide), rather than at the para position (4BP-TQS), display no allosteric agonist activity but retain PAM activity on α7 nAChRs, demonstrating the importance of the location of the halogen atom on pharmacological properties. Replacement of the bromine atom in 4BP-TQS with either a chlorine [4CP-TQS (4-(4-chloroophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] or an iodine atom [4IP-TQS (4-(4-iodoophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] results in compounds that have pharmacological properties characteristic of allosteric agonists but display differences in activation rates, in inactivation rates, and in levels of desensitization. In contrast, replacement of the bromine atom in 4BP-TQS with a fluorine atom [4FP-TQS (4-(4-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide)] generated a compound that lacks allosteric agonist activity but acts a potentiator of responses to acetylcholine. In addition, 4FP-TQS was found to act as an antagonist of responses evoked by allosteric agonists such as 4BP-TQS. These findings provide evidence of the pharmacological diversity of compounds interacting with the allosteric transmembrane site on α7 nAChRs.

Dataset Information

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

Publications

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

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