Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes' orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M-1, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their physicochemical property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood-brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM(1)-hM(5) were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM(1) in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds' structure-activity relationship and will guide the development towards highly selective mAChRs ligands.

Automated summary

The muscarinic acetylcholine receptor family is a highly sought-after target for neurological disorders. Despite previous failures to develop subtype-selective ligands, this study successfully synthesized a series of arecaidine-derived ligands with potential blood-brain barrier permeability and determined their binding affinities towards each of the individual human mAChR subtypes. The most promising compound of this series showed high selectivity towards hM(1) and acted as an antagonist. Overall, this study expands our understanding of the structure-activity relationship and provides guidance for the development of highly selective mAChR ligands.