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Ip messenger 4.066/24/2023 2 The representative structures of (A) ribophostin dimer 4, (B) homo and hetero dimers of IP 3 ( 5–10) and (C) dimers of 2-Bt-IP 4/IP 5 11. We therefore considered whether dimers of AdA might be more potent than AdA.įig. 18 These results demonstrate that dimeric IP 3R ligands can provide useful tools, some of which have greater affinity than the monomeric ligands. 2C) were shown to be antagonists of IP 3Rs. 13d Very recently, dimers of 2- O-Bt-IP 4/IP 5 ( 11, Fig. 2B), particularly those with short linkers, were shown to bind to IP 3R with increased affinity. Several homodimeric 16 and heterodimeric 17 ligands of IP 3 ( 5–10, Fig. 15 However, the potencies of the monomeric and polymeric ligands were rather similar. 2A) were synthesized, anticipating that if the spacing between the linked ligands was appropriate they might bind simultaneously to the four IP 3-binding sites. Before the location of the IP 3-binding sites within IP 3R was known, clustered bi- and tetra-dentate analogs of ribophostin ( 4, Fig. 4b,14Ī few multimeric ligands of IP 3R have been reported. 13 The former is unlikely for IP 3R because the orientation of the IP 3-binding sites within the tetrameric IP 3R is unlikely to allow simultaneous binding of two ligands linked by a short tether. 12 This can be due to simultaneous binding to more than one binding site or a statistical effect arising from the local increase in ligand concentration. Multimeric ligands often have greater affinity than monomeric ligands. The simplest analog, triazolophostin ( 3, Fig. ![]() 11 These potent analogs have substituted triazoles as adenine surrogates. We recently reported synthesis of a library of active AdA analogs, triazolophostins, by using a click chemistry approach. 8 Molecular docking 8j,m,9 and mutation studies 10 suggest that a cation–π interaction between the adenine moiety of AdA and Arg504 within the IBC contributes to the increased affinity of AdA. 7 AdA analogs with a nucleobase or base-surrogate are also more potent than IP 3. ![]() 1), binds to IP 3R with greater affinity than IP 3 and it is more potent than IP 3 in evoking Ca 2+ release. 6 The fungal metabolite, adenophostin A (AdA, 2, Fig. There is continuing interest in the development of potent agonists and antagonists of IP 3R. 1 The structures of IP 3 ( 1), adenophostin A ( 2) and triazolophostin ( 3). 3 More recently, structures of the N-terminal region (residues 1–604) 4 alongside a structure of the complete IP 3R derived from cryo-electron microscopy have begun to suggest how IP 3 binding might trigger the opening of the intrinsic pore of IP 3R. 2 High-resolution structures of the IP 3-binding core (IBC, residues 224–604) have defined the interactions of IP 3 with IP 3R. 1 IP 3R are large tetrameric proteins, within which IP 3 binding to each of the four subunits is required to initiate opening of the Ca 2+-permeable channel. ![]() 1) is an important secondary messenger that evokes Ca 2+ release from intracellular stores through its interaction with IP 3 receptors (IP 3R) in the endoplasmic reticulum. Introduction Inositol 1,4,5-trisphosphate (IP 3, 1, Fig. We evaluated the potency of these analogs to release Ca 2+ through type 1 IP 3R and established that the newly synthesized dimers are equipotent to AdA and triazolophostin. Here, we used click chemistry to synthesize four homodimeric analogs of triazolophostin, connected by oligoethylene glycol chains of different lengths. We previously synthesized traizolophostin, in which a simple triazole replaced the adenine of AdA, and showed it to be equipotent to AdA. Adenophostin A (AdA) is a potent agonist of IP 3R and since some dimeric analogs of IP 3R ligands are more potent than the corresponding monomer we considered whether dimeric AdA analogs might provide agonists with increased potency. There is considerable interest in developing novel ligands of IP 3R. ![]() Inositol 1,4,5-trisphosphate receptors (IP 3Rs) are tetrameric intracellular channels through which many extracellular stimuli initiate the Ca 2+ signals that regulate diverse cellular responses.
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