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

Abstract

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 M1, 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 hM1–hM5 were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM1 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.

Apo2ph4: A Versatile Workflow for the Generation of Receptor-based Pharmacophore Models for Virtual Screening

“…Due to our experience in the development of orthosteric antagonists targeting mAChRs, − we decided to qualitatively evaluate the predictive value of the apo2ph4 workflow using a crystal structure of M2 muscarinic acetylcholine receptor subtype (PDB-entry 3UON). It should be noted that neither 3UON nor any other muscarinic acetylcholine receptor was used during internal optimization.…”