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Article ; Online: Reanalysis of a μ opioid receptor crystal structure reveals a covalent adduct with BU72.

Munro, Thomas A

2023 Volume 21, Issue 1, Page(s) 213

Abstract: Background: The first crystal structure of the active μ opioid receptor (μOR) exhibited several unexplained features. The ligand BU72 exhibited many extreme deviations from ideal geometry, along with unexplained electron density. I previously showed ... ...

Abstract	Background: The first crystal structure of the active μ opioid receptor (μOR) exhibited several unexplained features. The ligand BU72 exhibited many extreme deviations from ideal geometry, along with unexplained electron density. I previously showed that inverting the benzylic configuration resolved these problems, establishing revised stereochemistry of BU72 and its analog BU74. However, another problem remains unresolved: additional unexplained electron density contacts both BU72 and a histidine residue in the N-terminus, revealing the presence of an as-yet unidentified atom. Results: These short contacts and uninterrupted density are inconsistent with non-covalent interactions. Therefore, BU72 and μOR form a covalent adduct, rather than representing two separate entities as in the original model. A subsequently proposed magnesium complex is inconsistent with multiple lines of evidence. However, oxygen fits the unexplained density well. While the structure I propose is tentative, similar adducts have been reported previously in the presence of reactive oxygen species. Moreover, known sources of reactive oxygen species were present: HEPES buffer, nickel ions, and a sequence motif that forms redox-active nickel complexes. This motif contacts the unexplained density. The adduct exhibits severe strain, and the tethered N-terminus forms contacts with adjacent residues. These forces, along with the nanobody used as a G protein substitute, would be expected to influence the receptor conformation. Consistent with this, the intracellular end of the structure differs markedly from subsequent structures of active μOR bound to G Conclusions: Later G
MeSH term(s)	Binding Sites ; Ligands ; Receptors, Opioid, mu/chemistry ; Receptors, Opioid, mu/metabolism ; Nickel/metabolism ; Reactive Oxygen Species/metabolism ; GTP-Binding Proteins/metabolism
Chemical Substances	Ligands ; Receptors, Opioid, mu ; Nickel (7OV03QG267) ; Reactive Oxygen Species ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2023-10-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/s12915-023-01689-w
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Article: Confirmation of the NMR assignments of salvinorin A.

Munro, Thomas A

Magnetic resonance in chemistry : MRC

2007 Volume 45, Issue 9, Page(s) 801

MeSH term(s)	Diterpenes/analysis ; Diterpenes, Clerodane ; Magnetic Resonance Spectroscopy ; Molecular Conformation ; Psychotropic Drugs/analysis ; Solutions
Chemical Substances	Diterpenes ; Diterpenes, Clerodane ; Psychotropic Drugs ; Solutions ; salvinorin A (T56W91NG6J)
Language	English
Publishing date	2007-09
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	1475029-6
ISSN	1097-458X ; 0749-1581
ISSN (online)	1097-458X
ISSN	0749-1581
DOI	10.1002/mrc.2020
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Article: Salvinorin B meth-oxy-methyl ether.

Munro, Thomas A / Ho, Douglas M / Cohen, Bruce M

Acta crystallographica. Section E, Structure reports online

2012 Volume 68, Issue Pt 11, Page(s) o3225–6

Abstract: The title compound [MOM-SalB; systematic name: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-fur-yl)-9-meth-oxy-meth-oxy-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octa-hydro-1H-benzo[f]isochromene-7-carboxyl-ate], C(23)H(30)O(8), is a deriv-ative of the κ- ...

Abstract	The title compound [MOM-SalB; systematic name: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-fur-yl)-9-meth-oxy-meth-oxy-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octa-hydro-1H-benzo[f]isochromene-7-carboxyl-ate], C(23)H(30)O(8), is a deriv-ative of the κ-opioid salvinorin A with enhanced potency, selectivity, and duration of action. Superimposition of their crystal structures reveals, surprisingly, that the terminal C and O atoms of the MOM group overlap with the corresponding atoms in salvinorin A, which are separated by an additional bond. This counter-intuitive isosterism is possible because the MOM ether adopts the 'classic anomeric' conformation (gauche-gauche), tracing a helix around the planar acetate of salvinorin A. This overlap is not seen in the recently reported structure of the tetra-hydro-pyranyl ether, which is less potent. The classic anomeric conformation is strongly favoured in alk-oxy-methyl ethers, but not in substituted acetals, which may contribute to their reduced potency. This structure may prove useful in evaluating models of the activated κ-opioid receptor.
Language	English
Publishing date	2012-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041947-8
ISSN	1600-5368
ISSN	1600-5368
DOI	10.1107/S1600536812043449
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Article: Salvinorins D-F, new neoclerodane diterpenoids from Salvia divinorum, and an improved method for the isolation of salvinorin A.

Munro, Thomas A / Rizzacasa, Mark A

Journal of natural products

2003 Volume 66, Issue 5, Page(s) 703–705

Abstract: Three new neoclerodane diterpenoids, salvinorins D-F (4-6), have been isolated from the leaves of Salvia divinorum. The structures were elucidated by chemical and spectroscopic methods, particularly 1D and 2D NMR. A simplified isolation method using ... ...

Abstract	Three new neoclerodane diterpenoids, salvinorins D-F (4-6), have been isolated from the leaves of Salvia divinorum. The structures were elucidated by chemical and spectroscopic methods, particularly 1D and 2D NMR. A simplified isolation method using chromatography on activated carbon also gave improved yields of the controlled substance salvinorin A (1) and of salvinorin C (3).
MeSH term(s)	Acetylation ; Animals ; Diterpenes/chemistry ; Diterpenes/isolation & purification ; Diterpenes/pharmacology ; Diterpenes, Clerodane ; Feeding Behavior/drug effects ; Mexico ; Molecular Structure ; Nuclear Magnetic Resonance, Biomolecular ; Salvia/chemistry ; Spodoptera/drug effects ; Tenebrio/drug effects
Chemical Substances	Diterpenes ; Diterpenes, Clerodane ; salvinorin D ; salvinorin E ; salvinorin F
Language	English
Publishing date	2003-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/np0205699
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Article: Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity.

Munro, Thomas A / Xu, Wei / Ho, Douglas M / Liu-Chen, Lee-Yuan / Cohen, Bruce M

Beilstein journal of organic chemistry

2013 Volume 9, Page(s) 2916–2924

Abstract: The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. ... ...

Abstract	The recent crystal structure of the κ-opioid receptor (κ-OR) revealed, unexpectedly, that the antagonist JDTic is a bivalent ligand: in addition to the orthosteric pocket occupied by morphinans, JDTic also occupies a distinct (allotopic) pocket. Mutagenesis data suggest that salvinorin A (1) also binds to this allotopic pocket, adjacent to the aspartate residue that anchors the basic nitrogen atom of classical opiates (Asp138). It has been suggested that an H-bond donor appended to 1 might interact with Asp138, increasing affinity. Such a bivalent ligand might also possess altered functional selectivity. Based on modeling and known N-furanylmethyl opioid antagonists, we appended H-bond donors to the furan ring of 1. (Dimethylamino)methyl groups at C-15 or C-16 abolished affinity for κ-OR. Hydroxymethylation at C-16 was tolerated, but 15,16-bis-hydroxymethylation was not. Since allosteric modulators may go undetected in binding assays, we also tested these and other low-affinity derivatives of 1 for allosteric modulation of dynorphin A in the [(35)S]GTPγS assay. No modulation was detected. As an alternative attachment point for bivalent derivatives, we prepared the 2-(hydroxyethoxy)methyl ether, which retained high affinity for κ-OR. We discuss alternative design strategies for linked, fused or merged bivalent derivatives of 1.
Language	English
Publishing date	2013-12-20
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2192461-2
ISSN	1860-5397
ISSN	1860-5397
DOI	10.3762/bjoc.9.328
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Article ; Online: Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons.

Schmid, Cullen L / Streicher, John M / Groer, Chad E / Munro, Thomas A / Zhou, Lei / Bohn, Laura M

The Journal of biological chemistry

2013 Volume 288, Issue 31, Page(s) 22387–22398

Abstract: There is considerable evidence to suggest that drug actions at the κ-opioid receptor (KOR) may represent a means to control pain perception and modulate reward thresholds. As a G protein-coupled receptor (GPCR), the activation of KOR promotes Gαi/o ... ...

Abstract	There is considerable evidence to suggest that drug actions at the κ-opioid receptor (KOR) may represent a means to control pain perception and modulate reward thresholds. As a G protein-coupled receptor (GPCR), the activation of KOR promotes Gαi/o protein coupling and the recruitment of β-arrestins. It has become increasingly evident that GPCRs can transduce signals that originate independently via G protein pathways and β-arrestin pathways; the ligand-dependent bifurcation of such signaling is referred to as "functional selectivity" or "signaling bias." Recently, a KOR agonist, 6'-guanidinonaltrindole (6'-GNTI), was shown to display bias toward the activation of G protein-mediated signaling over β-arrestin2 recruitment. Therefore, we investigated whether such ligand bias was preserved in striatal neurons. Although the reference KOR agonist U69,593 induces the phosphorylation of ERK1/2 and Akt, 6'-GNTI only activates the Akt pathway in striatal neurons. Using pharmacological tools and β-arrestin2 knock-out mice, we show that KOR-mediated ERK1/2 phosphorylation in striatal neurons requires β-arrestin2, whereas Akt activation depends upon G protein signaling. These findings reveal a point of KOR signal bifurcation that can be observed in an endogenous neuronal setting and may prove to be an important indicator when developing biased agonists at the KOR.
MeSH term(s)	Animals ; CHO Cells ; Corpus Striatum/cytology ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Cricetinae ; Cricetulus ; Guanidines/pharmacology ; MAP Kinase Signaling System ; Male ; Mice ; Naltrexone/analogs & derivatives ; Naltrexone/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Phosphorylation ; Receptors, Opioid, kappa/drug effects
Chemical Substances	6'-guanidinonaltrindole ; Guanidines ; Receptors, Opioid, kappa ; Naltrexone (5S6W795CQM)
Language	English
Publishing date	2013-06-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.476234
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Article ; Online: Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic

Munro Thomas A / Berry Loren M / Van’t Veer Ashlee / Béguin Cécile / Carroll F / Zhao Zhiyang / Carlezon William A / Cohen Bruce M

BMC Pharmacology, Vol 12, Iss 1, p

pharmacokinetics in mice and lipophilicity

2012 Volume 5

Abstract: Abstract Background Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell ...

Abstract	Abstract Background Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the κ opioid receptor. Methods To evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS). Results In each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of κ antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D 7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism. Conclusions The negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.
Keywords	Norbinaltorphimine ; Nor-BNI ; 5’-guanidinonaltrindole ; 5’-GNTI ; JDTic ; Pharmacokinetics ; Lipophilicity ; P-gp ; JNK1 ; MAPK8 ; Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R ; DOAJ:Therapeutics ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2012-05-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters.

Munro, Thomas A / Huang, Xi-Ping / Inglese, Carmela / Perrone, Maria Grazia / Van't Veer, Ashlee / Carroll, F Ivy / Béguin, Cécile / Carlezon, William A / Colabufo, Nicola A / Cohen, Bruce M / Roth, Bryan L

PloS one

2013 Volume 8, Issue 8, Page(s) e70701

Abstract: Background: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them ...

Abstract	Background: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. Results: In binding assays, the three antagonists showed no detectable affinity (K(i)≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α(2C)-adrenoceptor (K(i) = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α(1A)-adrenoceptor (EC₅₀ = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M₁ receptor antagonist (K(B) = 3.7 µM). JDTic bound to the noradrenaline transporter (K(i) = 54 nM), but only weakly inhibited transport (IC₅₀ = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (K(i) = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Conclusions: Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α(1A)-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists.
MeSH term(s)	Allosteric Regulation ; Biological Transport ; Caco-2 Cells ; Calcium/metabolism ; Guanidines/metabolism ; Guanidines/pharmacology ; Humans ; Kinetics ; Morphinans/metabolism ; Morphinans/pharmacology ; Naltrexone/analogs & derivatives ; Naltrexone/metabolism ; Naltrexone/pharmacology ; Narcotic Antagonists/metabolism ; Narcotic Antagonists/pharmacology ; Norepinephrine/metabolism ; Norepinephrine Plasma Membrane Transport Proteins/metabolism ; Piperidines/metabolism ; Piperidines/pharmacology ; Protein Binding ; Receptors, Adrenergic, alpha/metabolism ; Receptors, Opioid, delta/metabolism ; Receptors, Opioid, kappa/antagonists & inhibitors ; Receptors, Opioid, kappa/metabolism ; Receptors, Opioid, mu/metabolism ; Tetrahydroisoquinolines/metabolism ; Tetrahydroisoquinolines/pharmacology
Chemical Substances	17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan ; 7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide ; Guanidines ; Morphinans ; Narcotic Antagonists ; Norepinephrine Plasma Membrane Transport Proteins ; Piperidines ; Receptors, Adrenergic, alpha ; Receptors, Opioid, delta ; Receptors, Opioid, kappa ; Receptors, Opioid, mu ; Tetrahydroisoquinolines ; norbinaltorphimine (36OOQ86QM1) ; Naltrexone (5S6W795CQM) ; Calcium (SY7Q814VUP) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2013-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0070701
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Article: Autoxidation of salvinorin A under basic conditions.

Munro, Thomas A / Goetchius, Glenn W / Roth, Bryan L / Vortherms, Timothy A / Rizzacasa, Mark A

The Journal of organic chemistry

2005 Volume 70, Issue 24, Page(s) 10057–10061

Abstract: reaction: see text] Treatment of salvinorin A (1a) with KOH in MeOH gave the enedione 3, for which the dienone structure 7 was recently proposed. Also isolated, after methylation, were the secotriesters 4a-c. A mechanism for this unusual series of ... ...

Abstract	[reaction: see text] Treatment of salvinorin A (1a) with KOH in MeOH gave the enedione 3, for which the dienone structure 7 was recently proposed. Also isolated, after methylation, were the secotriesters 4a-c. A mechanism for this unusual series of autoxidations is proposed. Surprisingly, 4a showed weak affinity at the kappa-opioid receptor. Divinatorins A-C (2a-c) showed no affinity at opioid receptors. Attempted reduction of 3 to a novel salvinorin diol (9d) was unsuccessful, but careful deacetylation of salvinorin C (9a) provided a viable route to this compound. A general method for identifying salvinorin 8-epimers by TLC is also presented.
MeSH term(s)	Diterpenes/chemical synthesis ; Diterpenes/chemistry ; Diterpenes, Clerodane ; Hydroxides/chemistry ; Methanol/chemistry ; Molecular Conformation ; Oxidation-Reduction ; Potassium Compounds/chemistry ; Stereoisomerism
Chemical Substances	Diterpenes ; Diterpenes, Clerodane ; Hydroxides ; Potassium Compounds ; salvinorin A (T56W91NG6J) ; potassium hydroxide (WZH3C48M4T) ; Methanol (Y4S76JWI15)
Language	English
Publishing date	2005-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	123490-0
ISSN	1520-6904 ; 0022-3263
ISSN (online)	1520-6904
ISSN	0022-3263
DOI	10.1021/jo051813e
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Article: Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist.

Munro, Thomas A / Rizzacasa, Mark A / Roth, Bryan L / Toth, Beth A / Yan, Feng

Journal of medicinal chemistry

2005 Volume 48, Issue 2, Page(s) 345–348

Abstract: Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the ... ...

Abstract	Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.
MeSH term(s)	Animals ; Diterpenes/chemical synthesis ; Diterpenes/chemistry ; Diterpenes/pharmacology ; Diterpenes, Clerodane ; Radioligand Assay ; Rats ; Receptors, Opioid, kappa/agonists ; Structure-Activity Relationship
Chemical Substances	Diterpenes ; Diterpenes, Clerodane ; Receptors, Opioid, kappa ; salvinorin A (T56W91NG6J)
Language	English
Publishing date	2005-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm049438q
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