Salvinorin A: allosteric interactions at the mu-opioid receptor.

Salvinorin A: allosteric interactions at the mu-opioid receptor. Research Abstract Details 

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Salvinorin A: allosteric interactions at the mu-opioid receptor. Abstract Text:

Richard B Rothman,Daniel L Murphy,Heng Xu,Jonathan A Godin,Christina M Dersch,John S Partilla,Kevin Tidgewell,Matthew Schmidt,Thomas E Prisinzano,Richard B Rothman,Daniel L Murphy,Heng Xu,Jonathan A Godin,Christina M Dersch,John S Partilla,Kevin Tidgewell,Matthew Schmidt,Thomas E Prisinzano,

Salvinorin A [(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(3-furanyl)-dodecahydro-6a,10b-dimethyl-4,10-dioxo-2h-naphtho[2,1-c]pyran-7-carboxylic acid methyl ester] is a hallucinogenic kappa-opioid receptor agonist that lacks the usual basic nitrogen atom present in other known opioid ligands. Our first published studies indicated that Salvinorin A weakly inhibited mu-receptor binding, and subsequent experiments revealed that Salvinorin A partially inhibited mu-receptor binding. Therefore, we hypothesized that Salvinorin A allosterically modulates mu-receptor binding. To test this hypothesis, we used Chinese hamster ovary cells expressing the cloned human opioid receptor. Salvinorin A partially inhibited [(3)H]Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (0.5, 2.0, and 8.0 nM) binding with E(MAX) values of 78.6, 72.1, and 45.7%, respectively, and EC(50) values of 955, 1124, and 4527 nM, respectively. Salvinorin A also partially inhibited [(3)H]diprenorphine (0.02, 0.1, and 0.5 nM) binding with E(MAX) values of 86.2, 64, and 33.6%, respectively, and EC(50) values of 1231, 866, and 3078 nM, respectively. Saturation binding studies with [(3)H]DAMGO showed that Salvinorin A (10 and 30 microM) decreased the mu-receptor B(max) and increased the K(d) in a dose-dependent nonlinear manner. Saturation binding studies with [(3)H]diprenorphine showed that Salvinorin A (10 and 40 microM) decreased the mu-receptor B(max) and increased the K(d) in a dose-dependent nonlinear manner. Similar findings were observed in rat brain with [(3)H]DAMGO. Kinetic experiments demonstrated that Salvinorin A altered the dissociation kinetics of both [(3)H]DAMGO and [(3)H]diprenorphine binding to mu receptors. Furthermore, Salvinorin A acted as an uncompetitive inhibitor of DAMGO-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding. Viewed collectively, these data support the hypothesis that Salvinorin A allosterically modulates the mu-opioid receptor.

Salvinorin A: allosteric interactions at the mu-opioid receptor. Publishing Authors By Initials

RB Rothman,DL Murphy,H Xu,JA Godin,CM Dersch,JS Partilla,K Tidgewell,M Schmidt,TE Prisinzano,RB Rothman,DL Murphy,H Xu,JA Godin,CM Dersch,JS Partilla,K Tidgewell,M Schmidt,TE Prisinzano,

For similar proteins: membrane proteins: receptors, cell surface: receptors, g-protein-coupled: receptors, opioid: receptors, opioid, mu research abstracts see: proteins: membrane proteins: receptors, cell surface: receptors, g-protein-coupled: receptors, opioid: receptors, opioid, mu research

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Salvinorin A: allosteric interactions at the mu-opioid receptor. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: The Journal of pharmacology and experimental thera

VOLUME: 320

Page Numbers: 801-10

Journal Abbreviation: J. Pharmacol. Exp. Ther.

ISSN: 0022-3565

DAY: 23

MONTH: 10

YEAR: 2006

Salvinorin A: allosteric interactions at the mu-opioid receptor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 376362

Salvinorin A: allosteric interactions at the mu-opioid receptor. Keywords Mesh Terms:

KEYWORDS: Receptors, Opioid, mu

MESH TERMS: metabolism

Chemical & Substance for Abstract: Salvinorin A: allosteric interactions at the mu-opioid receptor. Information

Substance Name: salvinorin A

Registry Number: 83729-01-5

Grant and Affiliation Information for Salvinorin A: allosteric interactions at the mu-opioid receptor.

AFFILIATION: Clinical Psychopharmacology Section, Intramural Research Program, National Institute of Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. rrothman@mail.nih.gov

Country: United States

AGENCY: United States NIDA

GRANT: R01 DA018151-01A2

ACRONYM: DA

MEDLINETA: J Pharmacol Exp Ther

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