Semisynthetic neoclerodanes as kappa opioid receptor probes

Kimberly M. Lovell, Tamara Vasiljevik, Juan J. Araya, Anthony Lozama, Katherine M. Prevatt-Smith, Victor W. Day, Christina M. Dersch, Richard B. Rothman, Eduardo R. Butelman, Mary Jeanne Kreek, Thomas E. Prisinzano

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors.

Original languageEnglish
Pages (from-to)3100-3110
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number9
DOIs
StatePublished - May 1 2012

Bibliographical note

Funding Information:
The authors thank the National Institute on Drug Abuse (DA018151 to TEP, DA05130 to MJK, and DA011113 to ERB) and the NIH Dynamic Aspects of Chemical Biology training grant (GM008545 to KML and KPS) for financial support of ongoing research, and the National Science Foundation (CHE-0923449) and the University of Kansas for funds to purchase the x-ray instrumentation and computers. Portions of this work were supported by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health, or the National Science Foundation. The authors also thank Dr. Alfredo Ortega and Elihu Bautista for the pictures of Salvia sp.

Keywords

  • Furan
  • Hallucinogen
  • Kappa opioid receptor
  • Natural product
  • Salvia divinorum
  • Salvinorin A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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