Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists.

Muscarinic M receptor antagonists and inverse agonists displaying high affinity and subtype selectivity over the antitarget M are valuable pharmacological tools and may enable improved treatment of chronic obstructive pulmonary disease (COPD), asthma, or urinary incontinence. On the basis of known M antagonists comprising a piperidine or quinuclidine unit attached to a biphenyl carbamate, 5-fluoro substitution was responsible for M subtype selectivity over M, while 3'-chloro substitution substantially increased affinity through a σ-hole interaction. Resultantly, two piperidinyl- and two quinuclidinium-substituted biphenyl carbamates OFH243 (), OFH244 (), OFH3911 (), and OFH3912 () were discovered, which display two-digit picomolar affinities with values from 0.069 to 0.084 nM, as well as high selectivity over the M subtype (46- to 68-fold). While weak inverse agonistic properties were determined for the biphenyl carbamates and , neutral antagonism was observed for and and tiotropium under identical assay conditions.