Synthesis and evaluation of novel opioid ligands with a C-homomorphinan skeleton. Issue 10 (15th May 2016)

• Record Type: Journal Article
• Authors: Ishikawa, Kyoko; Mochizuki, Yusuke; Hirayama, Shigeto; Nemoto, Toru; Nagai, Kenichiro; Itoh, Kennosuke; Fujii, Hideaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 10(2016)
• Page Start: 2199
• Page End: 2205
• Publication Date: 2016-05-15
• Subjects: Opioid -- C-Homomorphinan -- δ Opioid receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.03.040
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 -Homomorphinan5 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 compound8 and quinoline compound9 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 compound12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound12 was the most selective δ receptor antagonist among the tested compounds.