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.

Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists.

Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.

[18F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and µ-Opioid Receptor.

18F-Labeled building blocks from the type of [18F]fluorophenylazocarboxylic-tert-butyl esters offer a rapid, mild, and reliable method for the 18F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the µ-opioid receptor, revealing compounds 3d and 3e with single-digit and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the µ-opioid receptor, but enhanced selectivity for the µ-subtype in comparison to the lead compound AH-7921. A "minimalist procedure" without the use of a cryptand and base for the preparation of 4-[18F]fluorophenylazocarboxylic-tert-butyl ester [18F]2a was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives ([18F]2b-f). With the substituted [18F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by 18F-fluoroarylation, namely the methoxy azocarboxamide [18F]3d as the D3 receptor radioligand and [18F]4a as a prototype structure of the µ-opioid receptor radioligand. By introducing the new series of [18F]fluorophenylazocarboxylic-tert-butyl esters, the method of 18F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of 18F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography .