title: Novel hydrolysis-resistant analogues of cyclic ADP-ribose: modification of the "northern" ribose and calcium release activity.
abstract: Three novel analogues modified in the "northern" ribose (ribose linked to N1 of adenine) of the Ca(2+) mobilizing second messenger cyclic adenosine diphosphoribose, termed 2"-NH(2)-cyclic adenosine diphosphoribose, cyclic adenosine diphospho-carbocyclic-ribose, and 8-NH(2)-cyclic adenosine diphospho-carbocyclic-ribose, were synthesized (chemoenzymatically and by total synthesis) and spectroscopically characterized, and the pK(a) values for the 6-amino/imino transition were determined in two cases. The biological activity of these analogues was determined in permeabilized human Jurkat T-lymphocytes. 2"-NH(2)-cyclic adenosine diphosphoribose mediated Ca(2+) release was slightly more potent than that of the endogenous cyclic adenosine diphosphoribose in terms of the concentration-reponse relationship. Both compounds released Ca(2+) from the same intracellular Ca(2+) pool. In addition, the control compound 2"-NH(2)-adenosine diphosphoribose was almost without effect. In contrast, only at much higher concentrations (> or =50 microM) did the "northern" carbocyclic analogue, cyclic adenosine diphospho-carbocyclic-ribose, significantly release Ca(2+) from permeabilized T cells, whereas the previously reported "southern" carbocyclic analogue, cyclic aristeromycin diphosphoribose, was slightly more active than the endogenous cyclic adenosine diphosphoribose. Likewise, 8-NH(2)-cyclic adenosine diphospho-carbocyclic-ribose, expected to antagonize Ca(2+) release as demonstrated previously for 8-NH(2)-cyclic adenosine diphosphoribose, did not inhibit cyclic adenosine diphosphoribose mediated Ca(2+) release. This indicates that the 2"-NH(2)-group substitutes well for the 2"-OH-group it replaces; it may be oriented toward the outside of the putative cyclic adenosine diphosphoribose receptor binding domain and/or it can potentially also engage in H bonding interactions with residues of that domain. In sharp contrast to this, replacement of the endocyclic furanose oxygen atom by CH(2) in a carbocyclic system obviously interferes with a crucial element of interaction between cyclic adenosine diphosphoribose and its receptor in T-lymphocytes.
authors.affiliation: Institute for Medical Biochemistry and Molecular Biology, Division of Cellular Signal Transduction, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. guse@uke.uni-hamburg.de
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
authors.forename: Céline
authors.initials: C
authors.lastname: Cakir-Kiefer
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.forename: Karin
authors.initials: K
authors.lastname: Weber
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Bailey
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Georg W
authors.initials: GW
authors.lastname: Mayr
authors.forename: Norman
authors.initials: N
authors.lastname: Oppenheimer
authors.forename: Francis
authors.initials: F
authors.lastname: Schuber
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D019169:Jurkat Cells; D007700:Kinetics; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: C439996:cyclic ADP-carbocyclic-ribose; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D002118:Calcium