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

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

Beilstein J. Org. Chem. 2013, 9, 2916–2924, doi:10.3762/bjoc.9.328

• , 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

• for linked, fused or merged bivalent derivatives of 1. Keywords: allotopic; bivalent ligand; designed multiple ligand; JDTic; κ-opioid receptor; natural products; Salvinorin A; Introduction The structure–activity relationships of salvinorin A (1), a potent and selective κ (kappa) opioid, have been

• selective antagonist JDTic is shown. Essential residues for high affinity binding of 1, where mutation reproducibly reduces affinity ≥10-fold, are shown with thick bonds for emphasis [7][8][9]. These key residues are all located in transmembrane helices (TMs) 2 and 7. The surfaces of these residues are