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Article: Naturally occurring 2′-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands

TitleNaturally occurring 2′-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2003
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/biochempharm
Citation
Biochemical Pharmacology, 2003, v. 66 n. 12, p. 2397-2407 How to Cite?
AbstractScreening of traditional medicines has proven invaluable to drug development and discovery. Utilizing activity-guided purification, we previously reported the isolation of a list of flavonoids from the medicinal herb Scutellaria baicalensis Georgi, one of which manifested an affinity for the benzodiazepine receptor (BDZR) comparable to that of the synthetic anxiolytic diazepam (K i=6.4nM). In the present study, this high-affinity, naturally occurring flavonoid derivative, 5,7,2′- trihydroxy-6,8-dimethoxyflavone (K36), was chosen for further functional and behavioral characterization. K36 inhibited [ 3H]flunitrazepam binding to native BDZR with a K i value of 6.05nM. In electrophysiological experiments K36 potentiated currents mediated by rat recombinant α 1β 2γ 2 GABA A receptors expressed in Xenopus oocytes. This potentiation was characterized by a threshold (1nM) and half-maximal stimulation (24nM) similar to diazepam. This enhancement was demonstrated to act via the BDZR, since co-application of 1μM of the BDZR antagonist Ro15-1788 reversed the potentiation. Oral administration of K36 produced significant BDZR-mediated anxiolysis in the mice elevated plus-maze, which was abolished upon co-administration of Ro15-1788. Sedation, myorelaxation and motor incoordination were not observed in the chosen dosage regimen. Structure-activity relationships utilizing synthetic flavonoids with different 2′ substituents on the flavone backbone supported that 2′-hydroxyl-substitution is a critical moiety on flavonoids with regard to BDZR affinities. These results further underlined the potential of flavonoids as therapeutics for the treatment of BDZR-associated syndromes. © 2003 Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/90795
ISSN
2015 Impact Factor: 5.091
2015 SCImago Journal Rankings: 2.263
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHuen, MSYen_HK
dc.contributor.authorHui, KMen_HK
dc.contributor.authorLeung, JWCen_HK
dc.contributor.authorSigel, Een_HK
dc.contributor.authorBaur, Ren_HK
dc.contributor.authorWong, JTFen_HK
dc.contributor.authorXue, Hen_HK
dc.date.accessioned2010-09-17T10:08:30Z-
dc.date.available2010-09-17T10:08:30Z-
dc.date.issued2003en_HK
dc.identifier.citationBiochemical Pharmacology, 2003, v. 66 n. 12, p. 2397-2407en_HK
dc.identifier.issn0006-2952en_HK
dc.identifier.urihttp://hdl.handle.net/10722/90795-
dc.description.abstractScreening of traditional medicines has proven invaluable to drug development and discovery. Utilizing activity-guided purification, we previously reported the isolation of a list of flavonoids from the medicinal herb Scutellaria baicalensis Georgi, one of which manifested an affinity for the benzodiazepine receptor (BDZR) comparable to that of the synthetic anxiolytic diazepam (K i=6.4nM). In the present study, this high-affinity, naturally occurring flavonoid derivative, 5,7,2′- trihydroxy-6,8-dimethoxyflavone (K36), was chosen for further functional and behavioral characterization. K36 inhibited [ 3H]flunitrazepam binding to native BDZR with a K i value of 6.05nM. In electrophysiological experiments K36 potentiated currents mediated by rat recombinant α 1β 2γ 2 GABA A receptors expressed in Xenopus oocytes. This potentiation was characterized by a threshold (1nM) and half-maximal stimulation (24nM) similar to diazepam. This enhancement was demonstrated to act via the BDZR, since co-application of 1μM of the BDZR antagonist Ro15-1788 reversed the potentiation. Oral administration of K36 produced significant BDZR-mediated anxiolysis in the mice elevated plus-maze, which was abolished upon co-administration of Ro15-1788. Sedation, myorelaxation and motor incoordination were not observed in the chosen dosage regimen. Structure-activity relationships utilizing synthetic flavonoids with different 2′ substituents on the flavone backbone supported that 2′-hydroxyl-substitution is a critical moiety on flavonoids with regard to BDZR affinities. These results further underlined the potential of flavonoids as therapeutics for the treatment of BDZR-associated syndromes. © 2003 Elsevier Inc. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/biochempharmen_HK
dc.relation.ispartofBiochemical Pharmacologyen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAllosteric Regulationen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBenzodiazepines - metabolismen_HK
dc.subject.meshDisease Models, Animalen_HK
dc.subject.meshFlavonoids - pharmacology - therapeutic useen_HK
dc.subject.meshGABA Modulators - pharmacologyen_HK
dc.subject.meshGABA-A Receptor Agonistsen_HK
dc.subject.meshLigandsen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMaze Learning - drug effectsen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Inbred ICRen_HK
dc.subject.meshPain - drug therapyen_HK
dc.subject.meshPain Measurement - drug effectsen_HK
dc.subject.meshRadioligand Assayen_HK
dc.subject.meshReceptors, GABA - metabolismen_HK
dc.subject.meshReceptors, GABA-A - metabolismen_HK
dc.subject.meshRecombinant Proteins - drug effects - metabolismen_HK
dc.titleNaturally occurring 2′-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligandsen_HK
dc.typeArticleen_HK
dc.identifier.emailHuen, MSY:huen.michael@hku.hken_HK
dc.identifier.authorityHuen, MSY=rp01336en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.bcp.2003.08.016en_HK
dc.identifier.pmid14637197-
dc.identifier.scopuseid_2-s2.0-0344154296en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0344154296&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume66en_HK
dc.identifier.issue12en_HK
dc.identifier.spage2397en_HK
dc.identifier.epage2407en_HK
dc.identifier.isiWOS:000186919000013-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridHuen, MSY=23004751500en_HK
dc.identifier.scopusauthoridHui, KM=7103304717en_HK
dc.identifier.scopusauthoridLeung, JWC=35934996400en_HK
dc.identifier.scopusauthoridSigel, E=7007154942en_HK
dc.identifier.scopusauthoridBaur, R=7103111366en_HK
dc.identifier.scopusauthoridWong, JTF=25939072200en_HK
dc.identifier.scopusauthoridXue, H=37041779000en_HK

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