Structure-Activity Relationships of Pan-Gαq/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators

Alice E. Berizzi, Aaron M. Bender, Craig W. Lindsley, P. Jeffrey Conn, Patrick M. Sexton, Christopher J. Langmead, Arthur Christopoulos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs). Using a combination of radioligand binding, functional inositol phosphate accumulation assays, receptor alkylation and operational data analysis, we show that most compounds in the series derive their variable potency and selectivity from differential cooperativity at the M1, M3 and M5 mAChRs. None of the PAMs showed greater than 10-fold subtype selectivity for the agonist-free receptor, but VU6007705, VU6007678, and VU6008555 displayed markedly increased cooperativity compared to the parent molecule and M5 mAChR-preferring PAM, ML380 (αβ > 100), in the presence of ACh. Most of the activity of these PAMs derives from their ability to potentiate ACh binding affinity at mAChRs, though VU6007678 was notable for also potentiating ACh signaling efficacy and robust allosteric agonist activity. These data provide key insights for the future design of more potent and subtype-selective mAChR PAMs.

Original languageEnglish
Pages (from-to)1818-1828
Number of pages11
JournalACS Chemical Neuroscience
Volume9
Issue number7
DOIs
Publication statusPublished - 18 Jul 2018

Keywords

  • affinity
  • cooperativity
  • efficacy
  • Muscarinic acetylcholine receptor
  • operational model
  • positive allosteric modulator

Cite this

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title = "Structure-Activity Relationships of Pan-Gαq/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators",
abstract = "Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of {"}pan-Gq-coupled{"} muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs). Using a combination of radioligand binding, functional inositol phosphate accumulation assays, receptor alkylation and operational data analysis, we show that most compounds in the series derive their variable potency and selectivity from differential cooperativity at the M1, M3 and M5 mAChRs. None of the PAMs showed greater than 10-fold subtype selectivity for the agonist-free receptor, but VU6007705, VU6007678, and VU6008555 displayed markedly increased cooperativity compared to the parent molecule and M5 mAChR-preferring PAM, ML380 (αβ > 100), in the presence of ACh. Most of the activity of these PAMs derives from their ability to potentiate ACh binding affinity at mAChRs, though VU6007678 was notable for also potentiating ACh signaling efficacy and robust allosteric agonist activity. These data provide key insights for the future design of more potent and subtype-selective mAChR PAMs.",
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Structure-Activity Relationships of Pan-Gαq/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators. / Berizzi, Alice E.; Bender, Aaron M.; Lindsley, Craig W.; Conn, P. Jeffrey; Sexton, Patrick M.; Langmead, Christopher J.; Christopoulos, Arthur.

In: ACS Chemical Neuroscience, Vol. 9, No. 7, 18.07.2018, p. 1818-1828.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Conn, P. Jeffrey

AU - Sexton, Patrick M.

AU - Langmead, Christopher J.

AU - Christopoulos, Arthur

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