Fischer O, Hofmann J, Rampp H, Kaindl J, Pratsch G, Bartuschat A, Taudte V, Fromm M, Hübner H, Gmeiner P, Heinrich M (2020)
Publication Type: Journal article
Publication year: 2020
Book Volume: 63
Pages Range: 4349-4369
Journal Issue: 8
DOI: 10.1021/acs.jmedchem.0c00297
Muscarinic M-3 receptor antagonists and inverse agonists displaying high affinity and subtype selectivity over the antitarget M-2 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-3 antagonists comprising a piperidine or quinuclidine unit attached to a biphenyl carbamate, S-fluoro substitution was responsible for M-3 subtype selectivity over M-2, while 3'-chloro substitution substantially increased affinity through a sigma-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 K-i values from 0.069 to 0.084 nM, as well as high selectivity over the M-2 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.
APA:
Fischer, O., Hofmann, J., Rampp, H., Kaindl, J., Pratsch, G., Bartuschat, A.,... Heinrich, M. (2020). Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. Journal of Medicinal Chemistry, 63(8), 4349-4369. https://doi.org/10.1021/acs.jmedchem.0c00297
MLA:
Fischer, Oliver, et al. "Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists." Journal of Medicinal Chemistry 63.8 (2020): 4349-4369.
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