Design, Synthesis, and Biological Evaluation of 4,4′-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4'-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico-chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM(1)-hM 5 , the most promising compound 2 displayed a high binding affinitiy towards hM(1)R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM(2-5)R (4-189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM(1)R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico-chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development.

Automated summary

Due to their important role in mediating physiological functions, finding subtype-selective ligands for muscarinic acetylcholine receptors (mAChRs) has been challenging. In this study, a series of 12 carbamates with the potential for blood-brain barrier permeation were identified through a docking campaign. Compound 2 showed high affinity for hM(1)R and selectivity against hM(2-5)R, making it a promising candidate for PET tracer development.