Nicotinic acid adenine dinucleotide phosphate analogues containing substituted nicotinic acid: effect of modification on Ca(2+) release

J Med Chem. 2010 Nov 11;53(21):7599-612. doi: 10.1021/jm1007209.

Abstract

Analogues of nicotinic acid adenine dinucleotide phosphate (NAADP) with substitution at either the 4- or the 5-position position of the nicotinic acid moiety have been synthesized from NADP enzymatically using Aplysia californica ADP-ribosyl cyclase or mammalian NAD glycohydrolase. Substitution at the 4-position of the nicotinic acid resulted in the loss of agonist potency for release of Ca(2+)-ions from sea urchin egg homogenates and in potency for competition ligand binding assays using [(32)P]NAADP. In contrast, several 5-substituted NAADP derivatives showed high potency for binding and full agonist activity for Ca(2+) release. 5-Azido-NAADP was shown to release calcium from sea urchin egg homogenates at low concentration and to compete with [(32)P]NAADP in a competition ligand binding assay with an IC(50) of 18 nM, indicating that this compound might be a potential photoprobe useful for specific labeling and identification of the NAADP receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-ribosyl Cyclase / chemistry
  • Animals
  • Aplysia / enzymology
  • Binding, Competitive
  • Calcium / metabolism*
  • Calcium Channel Agonists / chemical synthesis
  • Calcium Channel Agonists / pharmacology
  • Calcium Channel Blockers / chemical synthesis
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / metabolism
  • In Vitro Techniques
  • NAD+ Nucleosidase / chemistry
  • NADP / analogs & derivatives*
  • NADP / chemical synthesis
  • NADP / pharmacology
  • Niacin / analogs & derivatives*
  • Niacin / chemical synthesis*
  • Niacin / pharmacology
  • Radioligand Assay
  • Sea Urchins
  • Structure-Activity Relationship

Substances

  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Calcium Channels
  • Niacin
  • NADP
  • NAADP
  • ADP-ribosyl Cyclase
  • NAD+ Nucleosidase
  • Calcium