A unique binding epitope for salvinorin A, a non‐nitrogenous kappa opioid receptor agonist
Brian E. Kane, Marcelo J. Nieto, Christopher R Mccurdy, David M Ferguson
FEBS Journal May 1, 2006 DOI: 10.1111/j.1742-4658.2006.05212.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using chimeric and single-point mutant opioid receptors Peer reviewed |
|---|---|
| Population | Chimeric and mutant opioid receptors |
| Topics | Salvia divinorum |
| Key findings | Salvinorin A binds to a cluster of residues in TM II and VII, and a vertical alignment model between these helices is proposed. |
Abstract
Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non‐nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single‐point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL‐2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity.
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 17
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents. Molecules October 11, 2018
- Differential helical orientations among related G protein-coupled receptors provide a novel mechanism for selectivity. Studies with salvinorin A and the kappa-opioid receptor. Journal of Biological Chemistry February 2, 2007
- 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
- Investigating the Effects of Novel Kappa Opioid Receptor Agonists on the Dopamine Transporter 2011
and 12 more in the library
Cites 7
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Ethnopharmacology of ska María Pastora (Salvia divinorum, Epling and Játiva-M.). Journal of Ethnopharmacology May 1, 1983
- Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. Biochemistry June 21, 2005
- Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands. Journal of Medicinal Chemistry July 28, 2005
- Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2). Bioorganic & Medicinal Chemistry Letters June 1, 2005
and 2 more in the library