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
M3 receptor antagonists and inverse agonists
displaying high affinity and subtype selectivity over the antitarget
M2 are valuable pharmacological tools and may enable improved
treatment of chronic obstructive pulmonary disease (COPD), asthma,
or urinary incontinence. On the basis of known M3 antagonists
comprising a piperidine or quinuclidine unit attached to a biphenyl
carbamate, 5-fluoro substitution was responsible for M3 subtype selectivity over M2, while 3′-chloro substitution
substantially increased affinity through a σ-hole interaction.
Resultantly, two piperidinyl- and two quinuclidinium-substituted biphenyl
carbamates OFH243 (13n), OFH244 (13m), OFH3911
(14n), and OFH3912 (14m) were discovered,
which display two-digit picomolar affinities with Ki values from 0.069 to 0.084 nM, as well as high selectivity
over the M2 subtype (46- to 68-fold). While weak inverse
agonistic properties were determined for the biphenyl carbamates 13m and 13n, neutral antagonism was observed
for 14m and 14n and tiotropium under identical
assay conditions.