Discovery of Potent Positive Allosteric Modulators of the 伪3尾2 Nicotinic Acetylcholine Receptor by a Chemical Space Walk in ChEMBL

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• 作者：Justus J. B眉rgi ; Mahendra Awale ; Silvan D. Boss ; Tifany Schaer ; Fabrice Marger ; Juan M. Viveros-Paredes ; Sonia Bertrand ; J眉rg Gertsch ; Daniel Bertrand ; Jean-Louis Reymond
• 刊名：ACS Chemical Neuroscience
• 出版年：2014
• 出版时间：May 21, 2014
• 年：2014
• 卷：5
• 期：5
• 页码：346-359
• 全文大小：683K
• 年卷期：v.5,no.5(May 21, 2014)
• ISSN：1948-7193

文摘

While a plethora of ligands are known for the well studied 伪7 and 伪4尾2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related 伪3尾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 伪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 鈥渃hemical space walk鈥?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 伪3尾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.