Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor.
Feng Yan, Ruslan V Bikbulatov, Viorel Mocanu, Nedyalka Dicheva, Carol E Parker, William C. Wetsel, Philip D Mosier, Richard B Westkaemper, John A Allen, Jordan K Zjawiony, Bryan L. Roth
Biochemistry July 28, 2009 DOI: 10.1021/bi900605n (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Interventions | 22-thiocyanatosalvinorin A (RB-64) 22-chlorosalvinorin A (RB-48) |
| Topics | Salvia divinorum |
| Keywords | Kappa-opioid receptor Kor Receptor binding Receptor structure Receptor activation Drug discovery Medicinal chemistry Drug design Therapeutics Compound engineering Novel compounds Hallucinogen Natural product Psychoactive compound Structural biology Molecular modeling Protein structure Binding mechanism Receptor conformation Receptor active structure |
| Citations | 81 |
| Key findings | Novel salvinorin A-derived ligands RB-64 and RB-48 are extraordinarily potent and selective kappa-opioid receptor agonists that covalently bind to cysteine residue C315(7.38), providing direct evidence of a free cysteine in the agonist-bound state of the receptor. |
Abstract
Salvinorin A, the most potent naturally occurring hallucinogen, has attracted an increasing amount of attention since the kappa-opioid receptor (KOR) was identified as its principal molecular target by us [Roth, B. L., et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 11934-11939]. Here we report the design, synthesis, and biochemical characterization of novel, irreversible, salvinorin A-derived ligands suitable as active state probes of the KOR. On the basis of prior substituted cysteine accessibility and molecular modeling studies, C315(7.38) was chosen as a potential anchoring point for covalent labeling of salvinorin A-derived ligands. Automated docking of a series of potential covalently bound ligands suggested that either a haloacetate moiety or other similar electrophilic groups could irreversibly bind with C315(7.38). 22-Thiocyanatosalvinorin A (RB-64) and 22-chlorosalvinorin A (RB-48) were both found to be extraordinarily potent and selective KOR agonists in vitro and in vivo. As predicted on the basis of molecular modeling studies, RB-64 induced wash-resistant inhibition of binding with a strict requirement for a free cysteine in or near the binding pocket. Mass spectrometry (MS) studies utilizing synthetic KOR peptides and RB-64 supported the hypothesis that the anchoring residue was C315(7.38) and suggested one biochemical mechanism for covalent binding. These studies provide direct evidence of the presence of a free cysteine in the agonist-bound state of the KOR and provide novel insights into the mechanism by which salvinorin A binds to and activates the KOR.
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 10
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology June 1, 2010
- Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor. European journal of medicinal chemistry October 6, 2014
- Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands. Bioorganic & Medicinal Chemistry Letters May 15, 2013
- CoMFA analyses of C-2 position salvinorin A analogs at the kappa-opioid receptor provides insights into epimer selectivity. Journal of molecular graphics & modelling April 1, 2010
and 5 more in the library
Cites 10
- 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
- Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor. TIPS - Trends in Pharmacological Sciences March 1, 2003
- Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice. Journal of Pharmacology and Experimental Therapeutics August 1, 2006
- Salvinorin A: from natural product to human therapeutics. Molecular interventions October 1, 2006
and 5 more in the library