Synthesis and biological evaluation of C-2 halogenated analogs of salvinorin A.
David Y W Lee, Lu Yang, Wei Xu, Gang Deng, Lin Guo, Lee-Yuan Liu-Chen
Bioorganic & Medicinal Chemistry Letters October 1, 2010 DOI: 10.1016/j.bmcl.2010.08.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Key findings | C-2 halogenated analogs of salvinorin A did not improve KOPR binding affinity, and β isomers generally bind better than α isomers except for iodinated analogs. |
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.
Comparable studies
Other experimental studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. | 2002 | Experimental study | |
| Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells and... | 2004 | Experimental study | |
| Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Animal model | 2014 | Experimental study | |
| Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. | 2005 | Experimental study | |
| Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Rat brain striatum homogenates | 2009 | Laboratory experiment |
Citations in the library
Cited by 7
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A. MedChemComm December 1, 2011
- Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands. Bioorganic & Medicinal Chemistry Letters May 15, 2013
- Investigating the Effects of Novel Kappa Opioid Receptor Agonists on the Dopamine Transporter 2011
- Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor Preprints.org November 1, 2022
and 2 more in the library
Cites 13
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint, Salvia divinorum The Journal of Organic Chemistry November 1, 1984
- Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug and Alcohol Dependence November 8, 2006
- Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor. TIPS - Trends in Pharmacological Sciences March 1, 2003
- Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid. Journal of Pharmacology and Experimental Therapeutics February 1, 2009
and 8 more in the library