Cyclic ADP-ribose analogues containing the methylenebisphosphonate linkage: effect of pyrophosphate modifications on Ca2+ release activity

J Med Chem. 2005 Jun 16;48(12):4177-81. doi: 10.1021/jm049469l.

Abstract

Analogues of cyclic ADP-ribose (cADPR) incorporating a methylenebisphosphonate linkage in the place of the pyrophosphate have been synthesized from nicotinamide adenine dinucleotide analogues enzymatically using Aplysia californica ADP-ribosyl cyclase. Methylenebisphosphonate cyclic ADP-ribose (cADPR[CH(2)]) and methylenebisphosphonate cyclic 3-deaza-ADP-ribose (3-deaza-cADPR[CH(2)]) showed full agonist activity for release of Ca(2+) ions from sea urchin egg homogenates. The EC(50) for cADPR[CH(2)] was 856 nM and that for 3-deaza-cADPR[CH(2)] was 300 nM, about 15- and 5-fold less potent than cADPR, respectively.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP-ribosyl Cyclase / chemistry
  • Animals
  • Aplysia
  • Calcium / metabolism*
  • Catalysis
  • Cyclic ADP-Ribose / analogs & derivatives*
  • Cyclic ADP-Ribose / chemical synthesis*
  • Cyclic ADP-Ribose / chemistry
  • Cyclic ADP-Ribose / pharmacology
  • Diphosphonates / chemistry*
  • In Vitro Techniques
  • Sea Urchins

Substances

  • Diphosphonates
  • methylenebisphosphonate cyclic 3-deaza-ADP-ribose
  • methylenebisphosphonate cyclic ADP-ribose
  • Cyclic ADP-Ribose
  • ADP-ribosyl Cyclase
  • Calcium