title: Synthesis and biological evaluation of C-2 halogenated analogs of salvinorin A.
abstract: Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Based on the SAR, its C-2 position is one of the key binding sites and has very little space tolerance (3-4 carbons atoms) and limited to only lipophilic groups. In our attempt to prepare PET brain imaging agent for mapping KOPR, a series of C-2 halogenated analogs have been synthesized and screened for binding affinity at κ (KOPR), μ (MOPR), and δ (DOPR). These C-2 halogenated analogs with sequential changes of atomic radius and electron density serve as excellent molecular probes for further investigating the binding pocket at C-2, particularly on the effects of α verses β configuration at C-2 position. The results of KOPR binding and functional studies reveal β isomer in general binds better than α isomer with the exception of iodinated analogs and none of the C-2 halogenated analogs shows any improvement of KOPR binding affinity. Interestingly, functional assay has characterized that 6b is a partial agonist with E(max) of 46% of the kappa receptor full agonist U50,488H at 250 nM (K(i)). We have also observed that the affinity to the kappa receptor increases with atomic radius (I>Br>Cl>F) which is in good agreement with halogen bonding interactions reported in the literature.
authors.affiliation: Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. DLee@mclean.harvard.edu
authors.forename: David Y W
authors.initials: DY
authors.lastname: Lee
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Deng
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Lee-Yuan
authors.initials: LY
authors.lastname: Liu-Chen
mesh_terms: D045785:Diterpenes, Clerodane / Q000138:chemical synthesis* / Q000737:chemistry; D054879:Halogenation; D007536:Isomerism; D007700:Kinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D027544:Salvia / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; C090499:salvinorin A
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