Opioid Receptor Probes Derived from Cycloaddition of the Hallucinogen Natural Product Salvinorin A

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• 作者：Anthony Lozama ; Christopher W. Cunningham ; Michael J. Caspers ; Justin T. Douglas ; Christina M. Dersch ; Richard B. Rothman ; Thomas E. Prisinzano
• 刊名：Journal of Natural Products
• 出版年：2011
• 出版时间：April 25, 2011
• 年：2011
• 卷：74
• 期：4
• 页码：718-726
• 全文大小：893K
• 年卷期：v.74,no.4(April 25, 2011)
• ISSN：1520-6025

文摘

As part of our continuing efforts toward more fully understanding the structure鈭抋ctivity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels鈭扐lder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure鈭抋ctivity relationships of furan-containing natural products.