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.
Life sciences
October 15, 2004
Feng Yan, Bryan L Roth
68 citations
Salvinorin A, a natural hallucinogen, acts as a highly selective agonist at kappa-opioid receptors (KORs), which are the main site for dynorphin and related neuropeptides. This review summarizes the chemistry, pharmacology, and biology of salvinorin A. Because it profoundly alters consciousness and perception, studying how salvinorin A interacts with KORs may reveal new insights into the molecular and cellular basis of higher human cortical functions.