Biochemistry
June 21, 2005
Feng Yan, Philip D Mosier, Richard B Westkaemper et al.
91 citations
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, selectively and potently activates kappa-opioid receptors (KORs), making it the only known lipid-like molecule to do so and the only non-nitrogenous opioid receptor agonist. Key residues in KORs responsible for its high binding affinity and agonist efficacy were identified: interactions with tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119) stabilize salvinorin A in the binding pocket, while activation requires interactions with helix 7 tyrosines Tyr312, Tyr313, and Tyr320 and with Tyr139 in helix 3.
Biochemistry
July 28, 2009
Feng Yan, Ruslan V Bikbulatov, Viorel Mocanu et al.
81 citations
Salvinorin A, the most potent naturally occurring hallucinogen, targets the kappa-opioid receptor (KOR). Researchers designed and synthesized novel irreversible salvinorin A-derived ligands, RB-64 and RB-48, as active state probes of KOR. Based on molecular modeling, they targeted cysteine residue C315(7.38) for covalent binding. Both compounds were extraordinarily potent and selective KOR agonists in vitro and in vivo. RB-64 showed wash-resistant inhibition of binding requiring a free cysteine near the binding pocket. Mass spectrometry confirmed C315(7.38) as the anchoring residue and suggested a biochemical mechanism for covalent binding. These findings provide direct evidence of a free cysteine in the agonist-bound KOR state and insights into salvinorin A's binding and activation mechanism.
The Journal of biological chemistry
February 2, 2007
Timothy A Vortherms, Philip D Mosier, Richard B Westkaemper et al.
40 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, binds selectively and potently to the kappa-opioid receptor (KOR). Unlike most ligands for peptide-binding receptors, it is non-nitrogenous and lipid-like. Using chimeric receptors, mutagenesis, accessibility methods, and modeling, the study found that helix 2 of KOR is essential for binding, with two valine residues (Val-108 and Val-118) conferring selectivity. Modeling suggested these residues indirectly affect binding by rotating helix 2. Accessibility experiments comparing KOR and the delta-opioid receptor, which does not bind salvinorin A, showed differential water accessibility of key residues, indicating that differences in helix 2 orientation are critical for salvinorin A's selective binding to KOR.
European journal of medicinal chemistry
October 6, 2014
Prabhakar R Polepally, Krzysztof Huben, Eyal Vardy et al.
28 citations
Salvinorin A, a compound from the plant Salvia divinorum, binds strongly and selectively to the κ-opioid receptor (KOR). A new series of salvinorin A derivatives with reactive Michael acceptor groups at C-2 was created to explore how the compound interacts with the receptor. Most of these derivatives retained high affinity for KOR, and some also bound to the μ-opioid receptor (MOR). None showed wash-resistant irreversible binding. Using the KOR crystal structure, mutagenesis data, and other methods, the researchers identified possible ways the new compounds interact with both KOR and MOR.
Journal of molecular graphics & modelling
April 1, 2010
Donna L Mcgovern, Philip D Mosier, Bryan L Roth et al.
16 citations
A key insight reveals why particular Salvinorin A derivatives bind more effectively to specific brain receptors: their precise molecular shape matters. Scientists employed computational modeling to develop highly predictive models, showing how subtle structural changes at a crucial C-2 position influence binding. The findings pinpoint a specific binding mechanism for amine-containing versions, explaining why one molecular orientation (beta-epimers) consistently achieves stronger binding than another. This offers valuable insights for designing compounds with tailored receptor interactions.
The Journal of biological chemistry
November 29, 2013
Eyal Vardy, Philip D Mosier, Kevin J Frankowski et al.
The κ-opioid receptor (KOR) is activated by diverse agonists through both shared and distinct molecular mechanisms. By docking four chemically different ligands (dynorphin A, U-69593, salvinorin A, and an octahydroisoquinolinone carboxamide) into the antagonist-bound KOR crystal structure and testing 18 mutated positions, two classes of mutations were identified: those impairing receptor function mainly by reducing ligand binding, and those impairing function without strongly affecting binding. Mutations of the latter type were located at the binding site periphery and did not interact strongly with ligands. These “functional” residues, together with water molecules seen in the crystal structure, likely help transmit the agonist binding signal to conserved rotamer switches that trigger receptor activation.