Synthesis of dimeric analogs of adenophostin A that potently evoke Ca(2+) release through IP(3) receptors

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are tetrameric intracellular channels through which many extracellular stimuli initiate the Ca(2+) signals that regulate diverse cellular responses. There is considerable interest in developing novel ligands of IP(3)R. Adenophostin A (AdA) is a potent agonist of IP(3)R and since some dimeric analogs of IP(3)R 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 Ca(2+) through type 1 IP(3)R and established that the newly synthesized dimers are equipotent to AdA and triazolophostin.