Synthesis, Radiosynthesis and Biological Evaluation of Buprenorphine‐Derived Phenylazocarboxamides as Novel μ‐Opioid Receptor Ligands

Abstract

Targeted structural modifications have led to a novel type of buprenorphine‐derived opioid receptor ligand displaying an improved selectivity profile for the μ‐OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, without loss of OR binding affinity or subtype selectivity. This study further includes functional experiments pointing to weak partial agonist properties of the novel μ‐OR ligands, as well as docking and metabolism experiments. Finally, the unique bifunctional character of phenylazocarboxylates, herein serving as precursors for the azocarboxamide subunit, was exploited to demonstrate the accessibility of an 18 F‐fluorinated analogue.

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

“…For removal of the iron tricarbonyl group of 243, photolytic iron ligand exchange with acetonitrile (UV light, 40 • C, 2.5 h) provided oripavine (5) in 35% yield. In a second line of experiments (Figure 68) [211], the conjugated diene system of thebaine (4) in ring-C was protected in the form of hetero Diels-Alder adducts (244,245,246). Dihydrothiopyrane adducts (244,245,246) were formed in the cycloaddition reaction of thebaine (4) with thioformyl cyanide in an approximate ratio of 244:245:246 = 1:4:3.…”

“…In a second line of experiments (Figure 68) [211], the conjugated diene system of thebaine (4) in ring-C was protected in the form of hetero Diels-Alder adducts (244,245,246). Dihydrothiopyrane adducts (244,245,246) were formed in the cycloaddition reaction of thebaine (4) with thioformyl cyanide in an approximate ratio of 244:245:246 = 1:4:3. The thioaldehyde was generated in situ from the Bunte salt (sodium S-(cyanomethyl) sulfothioate) with triethylamine in the presence of CaCl 2 in benzene-methanol.…”

“…The main products were the 7-substituted regioisomers, the 7β-cyano-6,14-epithiomethano-(245, 50%), and the 7α-cyano-6,14-epithiomethanocompounds (246, 38%), but formation of the 8α-cyano (247, 12%) minor by-product was also detected. 3-O-Demethylation of the 7-substituted regioisomers (245,246) was performed by applying the methods described above for the demethylation of thebaine-iron tricarbonyl complex (242), with yields of 247 and 248 ranging between 50 and 85%. The highest yield was attained by application of BBr 3 (85%).…”

“…In 2020, Krüll et al [246] reported a study inspired by the high affinity (K i (µ-OR) = 0.7 nM) of the cinnamoyl derivative of the 7α-aminomethyl-N 17 -cyclopropylmethyl-6,14-ethenomorphinans (324b, Figure 84) previously synthesized by Derrick et al in 2000 [228]. They explored the possibility of the bioisosteric replacement of the cinnamide substructure with phenylazocarboxamides by combining both structural scaffolds.…”

“…Applying tert-butyl 4-fluorophenylazocarboxylate as the azo compound, the product N-(4-fluorophenyl)azocarboxamide (363, X = N, R = F) was obtained in 87% yield. The highest binding affinities (HEK 2935 cells) were found for the 4-fluoro (363, X = N, R = F, K i (µ-OR) = 1.5 nM, K i (κ-OR) = 10 nM, and K i (δ-OR) = 36 nM, thus a 7-fold selectivity over κ-OR = 6.7 and a 24-fold selectivity over δ-OR) and 4-bromo azocarboxamide derivatives (363, X = N, R = Br, K i (µ-OR) = 1.3 nM, K i (κ-OR) = 10 nM, and K i (δ-OR) = 28 nM, thus an 8-fold selectivity over κ-OR and 22-fold over δ-OR) [246]. Evaluation of 363 (X = N, R = F) in functional assays at µ-ORs showed it to have weak partial agonist properties.…”