title: Nicotinic Acid Adenine Dinucleotide Phosphate Analogues Substituted on the Nicotinic Acid and Adenine Ribosides. Effects on ReceptorMediated Ca²⁺ Release.
abstract: Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca(2+) releasing intracellular second messenger in both mammals and echinoderms. We report that large functionalized substituents introduced at the nicotinic acid 5-position are recognized by the sea urchin receptor, albeit with a 20-500-fold loss in agonist potency. 5-(3-Azidopropyl)-NAADP was shown to release Ca(2+) with an EC50 of 31 μM and to compete with NAADP for receptor binding with an IC50 of 56 nM. Attachment of charged groups to the nicotinic acid of NAADP is associated with loss of activity, suggesting that the nicotinate riboside moiety is recognized as a neutral zwitterion. Substituents (Br- and N3-) can be introduced at the 8-adenosyl position of NAADP while preserving high potency and agonist efficacy and an NAADP derivative substituted at both the 5-position of the nicotinic acid and at the 8-adenosyl position was also recognized although the agonist potency was significantly reduced.
authors.affiliation: †Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Avenue, Toledo Ohio 43614, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Trabbic
authors.affiliation: ‡Department of Pharmacology, University of Minnesota Medical School, 321 Church Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: ‡Department of Pharmacology, University of Minnesota Medical School, 321 Church Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Walseth
authors.affiliation: †Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Avenue, Toledo Ohio 43614, United States.
authors.forename: James T
authors.initials: JT
authors.lastname: Slama
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D012617:Sea Urchins / Q000378:metabolism*
chemical_list: D015335:Molecular Probes; D011506:Proteins; D009249:NADP; C024376:NAADP; D002118:Calcium
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