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Munro TA, Xu W, Ho DM, et al. Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity. Beilstein J Org Chem. 2013;9:2916-24doi: 10.3762/bjoc.9.328.
Munro, T. A., Xu, W., Ho, D. M., Liu-Chen, L. Y., & Cohen, B. M. (2013). Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity. Beilstein journal of organic chemistry, 92916-24. https://doi.org/10.3762/bjoc.9.328
Munro, Thomas A, et al. "Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity." Beilstein journal of organic chemistry vol. 9 (2013): 2916-24. doi: https://doi.org/10.3762/bjoc.9.328
Munro TA, Xu W, Ho DM, Liu-Chen LY, Cohen BM. Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity. Beilstein J Org Chem. 2013 Dec 20;9:2916-24. doi: 10.3762/bjoc.9.328. eCollection 2013 Dec 20. PMID: 24454571; PMCID: PMC3896271.
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Beilstein J Org Chem. 2013 Dec 20;9:2916-24. doi: 10.3762/bjoc.9.328. eCollection 2013 Dec 20.

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity.

Beilstein journal of organic chemistry

Thomas A Munro, Wei Xu, Douglas M Ho, Lee-Yuan Liu-Chen, Bruce M Cohen

Affiliations

  1. McLean Hospital, Belmont, MA 02478, USA and Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA ; School of Chemistry and Bio21 Institute, University of Melbourne, Parkville 3010, Australia.
  2. Center for Substance Abuse Research and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  3. Department of Chemistry and Chemical Biology, Harvard University, Cambridge MA 02138, USA.
  4. McLean Hospital, Belmont, MA 02478, USA and Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.

PMID: 24454571 PMCID: PMC3896271 DOI: 10.3762/bjoc.9.328

Abstract

The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A (1) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N-furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1. (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [(35)S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1.

Keywords: JDTic; Salvinorin A; allotopic; bivalent ligand; designed multiple ligand; natural products; κ-opioid receptor

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