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Article: Synthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ release

TitleSynthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ release
Authors
Issue Date1993
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcr
Citation
Biochimica Et Biophysica Acta - Molecular Cell Research, 1993, v. 1178 n. 3, p. 235-242 How to Cite?
AbstractCyclic ADP-ribose (cADPR) is a naturally-occurring metabolite of NAD+ that is as effective as inositol trisphosphate in mobilizing intracellular Ca2+. A series of analogs modified at the 8-position of the adenine group were synthesized for the investigation of the relationship between the structure of the metabolite and its Ca2+-mobilizing activity. Substitution with an amino group at the 8-position of the adenine ring produced an antagonist. The 1H-NMR spectrum of 8-amino-cADPR showed characteristics of that of cADPR and confirmed the replacement of the 8-proton. By itself, 8-amino-cADPR (150 nM) did not induce Ca2+ release from sea-urchin-egg homogenates but totally blocked cADPR (135 nM) from doing so. The effect was reversible, since high concentrations of cADPR could overcome the inhibition. Addition of 8-amino-cADPR to egg homogenates during the cADPR-induced Ca2+ release blocked the release immediately, demonstrating the effectiveness of the antagonist. Measurements of [32P]cADPR binding to its microsomal binding site showed that 8-amino-cADPR was as effective as cADPR itself in competing for the binding site. In addition to blocking cADPR from releasing Ca2+, 8-amino-cADPR also inhibited cADPR from potentiating Ca2+-release induced by either divalent cations or by caffeine. Two other 8-substituted analogs were also synthesized. Both 8-Br- and 8-azido-cADPR were also antagonists, although with less potency than 8-amino-cADPR. These results show that alterations at the 8-position of the adenine group do not inhibit cADPR from binding to its receptor but do eliminate the ability of the metabolite to activate the Ca2+-release mechanism.
Persistent Identifierhttp://hdl.handle.net/10722/171582
ISSN
2015 Impact Factor: 5.128
2015 SCImago Journal Rankings: 3.043
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWalseth, TFen_US
dc.contributor.authorLee, HCen_US
dc.date.accessioned2012-10-30T06:15:49Z-
dc.date.available2012-10-30T06:15:49Z-
dc.date.issued1993en_US
dc.identifier.citationBiochimica Et Biophysica Acta - Molecular Cell Research, 1993, v. 1178 n. 3, p. 235-242en_US
dc.identifier.issn0167-4889en_US
dc.identifier.urihttp://hdl.handle.net/10722/171582-
dc.description.abstractCyclic ADP-ribose (cADPR) is a naturally-occurring metabolite of NAD+ that is as effective as inositol trisphosphate in mobilizing intracellular Ca2+. A series of analogs modified at the 8-position of the adenine group were synthesized for the investigation of the relationship between the structure of the metabolite and its Ca2+-mobilizing activity. Substitution with an amino group at the 8-position of the adenine ring produced an antagonist. The 1H-NMR spectrum of 8-amino-cADPR showed characteristics of that of cADPR and confirmed the replacement of the 8-proton. By itself, 8-amino-cADPR (150 nM) did not induce Ca2+ release from sea-urchin-egg homogenates but totally blocked cADPR (135 nM) from doing so. The effect was reversible, since high concentrations of cADPR could overcome the inhibition. Addition of 8-amino-cADPR to egg homogenates during the cADPR-induced Ca2+ release blocked the release immediately, demonstrating the effectiveness of the antagonist. Measurements of [32P]cADPR binding to its microsomal binding site showed that 8-amino-cADPR was as effective as cADPR itself in competing for the binding site. In addition to blocking cADPR from releasing Ca2+, 8-amino-cADPR also inhibited cADPR from potentiating Ca2+-release induced by either divalent cations or by caffeine. Two other 8-substituted analogs were also synthesized. Both 8-Br- and 8-azido-cADPR were also antagonists, although with less potency than 8-amino-cADPR. These results show that alterations at the 8-position of the adenine group do not inhibit cADPR from binding to its receptor but do eliminate the ability of the metabolite to activate the Ca2+-release mechanism.en_US
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcren_US
dc.relation.ispartofBiochimica et Biophysica Acta - Molecular Cell Researchen_US
dc.subject.meshAdenosine Diphosphate Ribose - Analogs & Derivatives - Antagonists & Inhibitors - Chemical Synthesis - Chemistryen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCalcium - Metabolismen_US
dc.subject.meshCalcium Channel Blockers - Chemical Synthesisen_US
dc.subject.meshCyclic Adp-Riboseen_US
dc.subject.meshCyclic Amp - Analogs & Derivatives - Chemistry - Pharmacologyen_US
dc.subject.meshMagnetic Resonance Spectroscopyen_US
dc.subject.meshOocytes - Metabolismen_US
dc.subject.meshSea Urchinsen_US
dc.titleSynthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ releaseen_US
dc.typeArticleen_US
dc.identifier.emailLee, HC:leehc@hku.hken_US
dc.identifier.authorityLee, HC=rp00545en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/0167-4889(93)90199-Yen_US
dc.identifier.pmid8395888-
dc.identifier.scopuseid_2-s2.0-0027313269en_US
dc.identifier.volume1178en_US
dc.identifier.issue3en_US
dc.identifier.spage235en_US
dc.identifier.epage242en_US
dc.identifier.isiWOS:A1993LX80300001-
dc.publisher.placeNetherlandsen_US
dc.identifier.scopusauthoridWalseth, TF=7005424273en_US
dc.identifier.scopusauthoridLee, HC=26642959100en_US

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