Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity.
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.
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.
Thomas A
TA
Munro
Center for Substance Abuse Research and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Wei
W
Xu
Department of Chemistry and Chemical Biology, Harvard University, Cambridge MA 02138, USA.
Douglas M
DM
Ho
Center for Substance Abuse Research and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Lee-Yuan
LY
Liu-Chen
McLean Hospital, Belmont, MA 02478, USA and Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.
Bruce M
BM
Cohen
JDTic; Salvinorin A; allotopic; bivalent ligand; designed multiple ligand; natural products; κ-opioid receptor