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Issue 11, 2015
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A structure–activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor

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Abstract

Positive allosteric modulators (PAMs) targeting the M4 muscarinic acetylcholine receptor (mAChR) offer greater sub-type selectivity and unique potential as central nervous system agents through their novel mode of action to traditional orthosteric ligands. In an attempt to elucidate the molecular determinants of allostery mediated by the exemplar thienopyridine M4 mAChR PAM, LY2033298, we report herein a systematic structure–activity relationship (SAR) study investigating different linkage points, halogen replacements to examine size and electronic effects, and different substitution combinations on the thienopyridine scaffold. We applied an operational model of allosterism to determine values of functional affinity (KB), cooperativity (αβ) and intrinsic agonism (τB) for all compounds.

Graphical abstract: A structure–activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor

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Article information


Submitted
07 Aug 2015
Accepted
28 Sep 2015
First published
30 Sep 2015

Med. Chem. Commun., 2015,6, 1998-2003
Article type
Concise Article
Author version available

A structure–activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor

M. Szabo, T. Huynh, C. Valant, J. R. Lane, P. M. Sexton, A. Christopoulos and B. Capuano, Med. Chem. Commun., 2015, 6, 1998
DOI: 10.1039/C5MD00334B

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