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

Abstract	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.
Authors	Oliver Fischer, Josefa Hofmann, Hannelore Rampp, Jonas Kaindl, Gerald Pratsch, Amelie Bartuschat, R Verena Taudte, Martin F Fromm, Harald Hübner, Peter Gmeiner, Markus R Heinrich
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 8 Pg. 4349-4369 (04 23 2020) ISSN: 1520-4804 [Electronic] United States
PMID	32202101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Aminobiphenyl Compounds CHRM3 protein, human Halogens Muscarinic Agonists Muscarinic Antagonists Receptor, Muscarinic M3 2-aminodiphenyl
Topics	Aminobiphenyl Compounds (chemistry, pharmacology) Animals Caco-2 Cells Drug Inverse Agonism HEK293 Cells Halogens (chemistry, pharmacology) Humans Male Molecular Docking Simulation (methods) Muscarinic Agonists (chemistry, metabolism, pharmacology) Muscarinic Antagonists (chemistry, pharmacology) Protein Binding (physiology) Protein Structure, Secondary Rats Rats, Sprague-Dawley Receptor, Muscarinic M3 (agonists, antagonists & inhibitors, metabolism)

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