title: Convergent synthesis and unexpected Ca(2+)-mobilizing activity of 8-substituted analogues of cyclic ADP-carbocyclic-ribose, a stable mimic of the Ca(2+)-mobilizing second messenger cyclic ADP-ribose.
abstract: Cyclic ADP-carbocyclic-ribose (cADPcR, 2) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. In this study, a series of 8-substituted analogues of cADPcR, namely the 8-chloro analogue 6 (8-Cl-cADPcR), the 8-azido analogue 7 (8-N(3)-cADPcR), the 8-amino analogue 8 (8-NH(2)-cADPcR), and the 8-phenylthio analogue 9 (8-SPh-cADPcR), were designed as effective pharmacological tools for studies on cADPR-modulated Ca(2+) signaling pathways. These target compounds were synthesized by a convergent route via 8-Cl-cADPcR bisacetonide (14) as the common intermediate, in which a method for forming the intramolecular pyrophosphate linkage by activation of the phenylthiophosphate type substrate 15 with AgNO(3) to produce 14 was used as the key step. The carbocyclic analogues were tested for activity in the sea urchin egg homogenate system. Compounds were assessed for their calcium-mobilizing effects and their ability to cross-desensitize with calcium release induced by a normally maximal concentration of cADPR, as well as cADPR antagonism of cADPR-evoked calcium release. While cADPcR was 3-4 times more potent than cADPR, the 8-substituted analogues were less efficacious, with 8-SPh-cADPcR largely acting as a competitive antagonist. Most surprisingly, given that 8-N(3)-cADPR and 8-NH(2)-cADPR are known as potent antagonists, 8-N(3)-cADPcR and 8-NH(2)-cADPcR were full agonists, but ca. 80 and 2 times less potent than cADPR, respectively. These data contribute to developing structure-activity relationships for the interaction of cADPR with its receptor.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. shu@pharm.hokudai.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudoh
authors.forename: Clive
authors.initials: C
authors.lastname: Garnham
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D018716:Molecular Mimicry; D010063:Ovum / Q000187:drug effects / Q000378:metabolism; D012617:Sea Urchins; D013329:Structure-Activity Relationship
chemical_list: C439996:cyclic ADP-carbocyclic-ribose; D036563:Cyclic ADP-Ribose; D002118:Calcium