A series of α7 nicotinic acetylcholine receptor allosteric modulators with close chemical similarity but diverse pharmacological properties.

Molecular Pharmacology
JasKiran K GillNeil S Millar

Abstract

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...Continue Reading

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Citations

Nov 17, 2015·Journal of Chemical Information and Modeling·Giovanni GraziosoAndrea Cavalli
Sep 1, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Patricio Iturriaga-VásquezMiguel Reyes-Parada
May 11, 2016·Future Medicinal Chemistry·Manuel CriadoRosario González-Muñiz
Aug 24, 2016·Expert Opinion on Drug Discovery·Miguel Reyes-Parada, Patricio Iturriaga-Vasquez
Mar 7, 2017·British Journal of Pharmacology·Cecilia Bouzat, Steven M Sine
Aug 2, 2015·Biochemical Pharmacology·Anna Chatzidaki, Neil S Millar
Oct 24, 2014·Molecular Pharmacology·Stuart J LansdellNeil S Millar
Feb 17, 2018·Future Medicinal Chemistry·Dina ManettiMaria Novella Romanelli
Mar 9, 2020·Neuropharmacology·Roger L Papke, Jon M Lindstrom
Jul 25, 2021·Pharmacological Reviews·Roger L Papke, Nicole A Horenstein
Aug 2, 2020·Neuropharmacology·Alican Gulsevin
Apr 10, 2019·Chemical Reviews·Isravel MuthukrishnanJ Carlos Menéndez

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