Synthesis and evaluation of novel opioid ligands with a C-homomorphinan skeleton

• Published in: Bioorganic & medicinal chemistry 2016-05, Vol.24 (10), p.2199-2205
• Main Authors: Ishikawa, Kyoko, Mochizuki, Yusuke, Hirayama, Shigeto, Nemoto, Toru, Nagai, Kenichiro, Itoh, Kennosuke, Fujii, Hideaki
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacology; Animals; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - chemistry; Benzylidene Compounds - pharmacology; C-Homomorphinan; CHO Cells; Cricetulus; Humans; Ligands; Models, Molecular; Morphinans - chemical synthesis; Morphinans - chemistry; Morphinans - pharmacology; Naltrexone - analogs & derivatives; Naltrexone - chemical synthesis; Naltrexone - chemistry; Naltrexone - pharmacology; Narcotic Antagonists - chemical synthesis; Narcotic Antagonists - chemistry; Narcotic Antagonists - pharmacology; Opioid; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Receptors, Opioid - metabolism; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - metabolism; Structure-Activity Relationship; δ Opioid receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.03.040

[Display omitted] As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds.