Functional Evaluation of Tetrahydroisoquinoline-Derived Ligands Reveals Distinct Modulatory Profiles at the Muscarinic M1 Receptor

The muscarinic acetylcholine M1 receptor (M1-mAChR) is a key regulator of cognitive processes and remains an attractive target for the modulation of central cholinergic signaling. In this study, tetrahydroisoquinoline-derived ligands (THQ140, THQ790) and a structurally related compound (QPB) were evaluated for their ability to modulate M1-mAChR activity. Intracellular Ca2+ imaging in HEK-293 cells expressing human M1-mAChR revealed distinct functional profiles, including partial agonist activity and limited or noncooperative modulation of ACh-induced signaling. In contrast to the prototypical M1 positive allosteric modulator benzyl quinolone carboxylic acid (BQCA), which displays minimal intrinsic agonism and strong positive cooperativity with ACh, the compounds reported here exhibited direct receptor activation with weaker or absent potentiation. Molecular docking and molecular dynamics simulations supported preferential interaction at a nonorthosteric region of the receptor. In addition, analysis of single-nucleus RNA sequencing data sets confirmed robust CHRM1 expression in neuronal populations of healthy and Alzheimer’s disease brains, supporting the continued relevance of M1-mAChR as a pharmacological target.