Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes S

Sophie J. Bradley, Colin Molloy, Christoffer Bundgaard, Adrian J. Mogg, Karen J. Thompson, Louis Dwomoh, Helen E. Sanger, Michael D. Crabtree, Simon M. Brooke, Patrick M. Sexton, Christian C. Felder, Arthur Christopoulos, Lisa M. Broad, Andrew B. Tobin, Christopher J. Langmead

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

The realization of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (mAChR) for the treatment of cognitive decline in Alzheimer’s disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1H-benzimidazol-2-one), described previously as a potent M1 receptor allosteric agonist, which showed procognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702, together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. Although they impart beneficial effects on learning and memory, we conclude that these properties are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data support the notion that “pure” positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses.

Original languageEnglish
Pages (from-to)645-656
Number of pages12
JournalMolecular Pharmacology
Volume93
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Cite this

Bradley, Sophie J. ; Molloy, Colin ; Bundgaard, Christoffer ; Mogg, Adrian J. ; Thompson, Karen J. ; Dwomoh, Louis ; Sanger, Helen E. ; Crabtree, Michael D. ; Brooke, Simon M. ; Sexton, Patrick M. ; Felder, Christian C. ; Christopoulos, Arthur ; Broad, Lisa M. ; Tobin, Andrew B. ; Langmead, Christopher J. / Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes S. In: Molecular Pharmacology. 2018 ; Vol. 93, No. 6. pp. 645-656.
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abstract = "The realization of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (mAChR) for the treatment of cognitive decline in Alzheimer’s disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1H-benzimidazol-2-one), described previously as a potent M1 receptor allosteric agonist, which showed procognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702, together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. Although they impart beneficial effects on learning and memory, we conclude that these properties are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data support the notion that “pure” positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses.",
author = "Bradley, {Sophie J.} and Colin Molloy and Christoffer Bundgaard and Mogg, {Adrian J.} and Thompson, {Karen J.} and Louis Dwomoh and Sanger, {Helen E.} and Crabtree, {Michael D.} and Brooke, {Simon M.} and Sexton, {Patrick M.} and Felder, {Christian C.} and Arthur Christopoulos and Broad, {Lisa M.} and Tobin, {Andrew B.} and Langmead, {Christopher J.}",
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doi = "10.1124/mol.118.111872",
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Bradley, SJ, Molloy, C, Bundgaard, C, Mogg, AJ, Thompson, KJ, Dwomoh, L, Sanger, HE, Crabtree, MD, Brooke, SM, Sexton, PM, Felder, CC, Christopoulos, A, Broad, LM, Tobin, AB & Langmead, CJ 2018, 'Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes S', Molecular Pharmacology, vol. 93, no. 6, pp. 645-656. https://doi.org/10.1124/mol.118.111872

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes S. / Bradley, Sophie J.; Molloy, Colin; Bundgaard, Christoffer; Mogg, Adrian J.; Thompson, Karen J.; Dwomoh, Louis; Sanger, Helen E.; Crabtree, Michael D.; Brooke, Simon M.; Sexton, Patrick M.; Felder, Christian C.; Christopoulos, Arthur; Broad, Lisa M.; Tobin, Andrew B.; Langmead, Christopher J.

In: Molecular Pharmacology, Vol. 93, No. 6, 01.06.2018, p. 645-656.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bradley, Sophie J.

AU - Molloy, Colin

AU - Bundgaard, Christoffer

AU - Mogg, Adrian J.

AU - Thompson, Karen J.

AU - Dwomoh, Louis

AU - Sanger, Helen E.

AU - Crabtree, Michael D.

AU - Brooke, Simon M.

AU - Sexton, Patrick M.

AU - Felder, Christian C.

AU - Christopoulos, Arthur

AU - Broad, Lisa M.

AU - Tobin, Andrew B.

AU - Langmead, Christopher J.

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