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

Monika Szabo; Tracey Huynh; Celine Valant; J Robert Lane; Patrick M Sexton; Arthur Christopoulos; Ben Capuano

doi:10.1039/c5md00334b

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

Monika Szabo, Tracey Huynh, Celine Valant, J Robert Lane, Patrick M Sexton, Arthur Christopoulos, Ben Capuano

Research output: Contribution to journal › Article › Research › peer-review

12 Citations (Scopus)

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 (K_B), cooperativity (αβ) and intrinsic agonism (τB) for all compounds.

Original language	English
Pages (from-to)	1998-2003
Number of pages	6
Journal	MedChemComm
Volume	6
Issue number	11
DOIs	https://doi.org/10.1039/c5md00334b
Publication status	Published - 2015

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10.1039/c5md00334b

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title = "A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor",

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.",

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AU - Szabo, Monika

AU - Huynh, Tracey

AU - Valant, Celine

AU - Lane, J Robert

AU - Sexton, Patrick M

AU - Christopoulos, Arthur

AU - Capuano, Ben

PY - 2015

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AB - 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.

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DO - 10.1039/c5md00334b

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

Abstract

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The Janus face of G Protein-Coupled Receptors: Implications for Disease Mechanisms and Opportunities for Drug Discovery

Novel Approaches to the Targeting of GPCRs towards Improved Treatment of Schizophrenia

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

Abstract

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The Janus face of G Protein-Coupled Receptors: Implications for Disease Mechanisms and Opportunities for Drug Discovery

Novel Approaches to the Targeting of GPCRs towards Improved Treatment of Schizophrenia

Rational Co-targeting of G protein-coupled receptors as a novel approach towards treating neuropsychiatric disorders

Cite this

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