A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans

Abstract

The 5-(3-hydroxy)phenylmorphan structural class of compounds are unlike the classical morphinans, 4,5-epoxymorphinans, and 6,7-benzomorphans, in that they have an equatorially oriented aromatic ring rather than the axial orientation of that ring found in the classical opioids. This modified and simplified opioid-like structure has been shown to retain antinociceptive activity, depending on its stereochemistry and substituents, and some of them have been found to be much more potent than morphine. A simple C9-hydroxy-5-(3-hydroxy)phenylmorphan enantiomer was found to be about 500 times more potent than morphine in vivo. We have previously examined C9-alkenyl and hydroxyalkyl substituents in the N-phenethyl-5-(3-hydroxy)phenylmorphan class of compounds. Comparable C9-alkyl (methyl through butyl) substituents, with their sets of diastereomers, have not been explored. All these compounds have now been synthesized to determine the effect chain-length and stereochemistry at the C9 position in the molecule might have on their interaction with opioid receptors. We now report the synthesis and in vitro activity of 16 compounds, the C9-methyl, ethyl, propyl, and butyl diastereomers, using the inhibition of forskolin-induced cAMP accumulation assay. Several potent (sub-nanomolar and nanomolar) MOR compounds were found to be selective agonists with varying efficacy. Of greatest interest, a selective MOR antagonist was discovered; it did not display any DOR or KOR agonist activity in vitro, was three times more potent than naltrexone, and was found to antagonize the EC90 of fentanyl at MOR to a greater extent than naltrexone.

Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans

“…We have developed a library of N-phenethyl-5-(3-hydroxyphenyl)morphan stereoisomers with a variety of substituents at the C9 position [4][5][6][7]. As additions to this library, we Molecules 2024, 29, 1926 3 of 33 have now synthesized amines separated from the C9 position by zero or one carbon atom, as well as two enantiomeric oximes at C9 and unsaturated and saturated cyano derivatives at C9.…”

“…The enantiomeric (1S,5S-and 1R,5R-) 9-keto-m-methoxyphenylmorphans were obtained using the literature procedure [7,15]. Reductive amination was found to allow the synthesis of C9 amino derivatives with zero carbons at C9, while the HWE reaction facilitates the formation of unsaturated and saturated cyano derivatives.…”

“…1 H-NMR (400 MHz; CDCl 3 ): δ 7.29-6.82 (m, 6H), 6.79-6.70 (m, 2H), 6.69-6.68 (m, 1H), 3.50 (s, 1H), 3.12-2.95 (m, 3H), 2.85-2.74 (m, 4H), 2.33-2.21 (m, 2H), 2.10 (dd, J = 13.6, 4.1 Hz, 1H), 1.96-1.84 (m, 2H), 1.77-1.62 (m, 2H), 1.51-1.48 (m, 1H). 13 (1S,5S,9R)-5-(3-Methoxyphenyl)-N-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-amine (7). In a pressure flask, the oxide 1 (300 mg, 0.858 mmol, 1 equiv), MeNH 2 •HCl (232 mg, 3.42 mmol, 4 equiv), triethylamine (480 mL, 3.43 mmol, 4 equiv), Ti(OiPr) 4 (1.01 mL, 3.42 mmol, 4 equiv), and EtOH (3 mL) were combined and heated to 50 • C overnight.…”

“…Molecules 2024, 29, 1926 2 of 33 found full or partial agonists with varied potency [3][4][5][6][7] at the µ-opioid receptor (MOR). Different ligands at the C9 position of the 5-phenylmorphan or compounds with a specific stereochemistry can interact with an active conformation of the receptor as a MOR agonist and turn on involved intracellular pathways [8] or act at the inactive conformation of the MOR as an opioid antagonist [5].…”