Restoring Agonist Function at a Chemogenetically Modified M1Muscarinic Acetylcholine Receptor

Elham Khajehali, Sophie Bradley, Emma T. Van Der Westhuizen, Colin Molloy, Celine Valant, Lisa Finlayson, Craig W. Lindsley, Patrick M. Sexton, Andrew B. Tobin, Arthur Christopoulos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) have been successfully employed to activate signaling pathways associated with specific muscarinic acetylcholine receptor (mAChR) subtypes. The M1 DREADD mAChR displays minimal responsiveness to the endogenous agonist acetylcholine (ACh) but responds to clozapine-N-oxide (CNO), an otherwise pharmacologically inert ligand. We have previously shown that benzyl quinolone carboxylic acid (BQCA), an M1 mAChR positive allosteric modulator (PAM), can rescue ACh responsiveness at these receptors. However, whether this effect is chemotype specific or applies to next-generation M1 PAMs with distinct scaffolds is unknown. Here, we reveal that new M1 PAMs restore ACh function at the M1 DREADD while modulating ACh binding at the M1 wild-type mAChR. Importantly, we demonstrate that the modulation of ACh function by M1 PAMs is translated in vivo using transgenic M1 DREADD mice. Our data provide important insights into mechanisms that define allosteric ligand modulation of agonist affinity vs efficacy and how these effects play out in the regulation of in vivo responses.

Original languageEnglish
Pages (from-to)4270–4279
Number of pages10
JournalACS Chemical Neuroscience
Volume11
Issue number24
DOIs
Publication statusPublished - 16 Dec 2020

Keywords

  • Allosteric modulation
  • BQCA
  • DREADD
  • Locomotor activity
  • Mmuscarinic acetylcholine receptor
  • PAM

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