Journal article

Restoring Agonist Function at a Chemogenetically Modified M-1 Muscarinic 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

ACS CHEMICAL NEUROSCIENCE | AMER CHEMICAL SOC | Published : 2020

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 rev..

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