Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator Lacking Cholinergic Adverse Effects.

Huong TM Nguyen; Elham Khajehali; Vi Pham; John W Scott; Toby A Dite; Laura F Dagley; James M Murphy; Geoff Thompson; Andrew B Tobin; David M Thal; Arthur Christopoulos; Emma T van der Westhuizen; Celine Valant

Journal article

Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator Lacking Cholinergic Adverse Effects.

Huong TM Nguyen, Elham Khajehali, Vi Pham, John W Scott, Toby A Dite, Laura F Dagley, James M Murphy, Geoff Thompson, Andrew B Tobin, David M Thal, Arthur Christopoulos, Emma T van der Westhuizen, Celine Valant

ACS Chem Neurosci | Published : 2026

DOI: 10.1021/acschemneuro.6c00229

Abstract

Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) have progressed into clinical trials for cognitive disorders, such as Alzheimer's disease and schizophrenia. However, their successful translation has been limited by on-target cholinergic adverse effects. These limitations have been attributed to excessive allosteric agonism, however, the contribution of allosteric cooperativity, efficacy modulation and receptor regulatory mechanisms remains poorly defined. Here, we performed a comparative pharmacological analysis of five structurally distinct M1 PAMs (BQCA, MK-7622, PF-06767832, MIPS1780 and VU0486846) in HEK293A cells expressing the human M1 mAChR (h..

View full abstract