Synthesis of dimeric analogs of adenophostin A that potently evoke Ca²⁺ release through IP₃ receptors

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are tetrameric intracellular channels through which many extracellular stimuli initiate the Ca²⁺ signals that regulate diverse cellular responses. There is considerable interest in developing novel ligands of IP₃R. Adenophostin A (AdA) is a potent agonist of IP₃R and since some dimeric analogs of IP₃R ligands are more potent than the corresponding monomer; we considered whether dimeric AdA analogs might provide agonists with increased potency. We previously synthesized traizolophostin, in which a simple triazole replaced the adenine of AdA, and showed it to be equipotent to AdA. Here, we used click chemistry to synthesize four homodimeric analogs of triazolophostin, connected by oligoethylene glycol chains of different lengths. We evaluated the potency of these analogs to release Ca²⁺ through type 1 IP₃R and established that the newly synthesized dimers are equipotent to AdA and triazolophostin.