Probing the Ca2+ mobilizing properties on primary cortical neurons of a new stable cADPR mimic

Abstract

Cyclic adenosine diphosphate ribose (cADPR) is a second messenger involved in the Ca²⁺ homeostasis. Its chemical instability prompted researchers to tune point by point its structure, obtaining stable analogues featuring interesting biological properties. One of the most challenging derivatives is the cyclic inosine diphosphate ribose (cIDPR), in which the hypoxanthine isosterically replaces the adenine. As our research focuses on the synthesis of N1 substituted inosines, in the last few years we have produced new flexible cIDPR analogues, where the northern ribose has been replaced by alkyl chains. Interestingly, some of them mobilized Ca²⁺ ions in PC12 cells. To extend our SAR studies, herein we report on the synthesis of a new stable cIDPR derivative which contains the 2″S,3″R dihydroxypentyl chain instead of the northern ribose. Interestingly, the new cyclic derivative and its open precursor induced an increase in intracellular calcium concentration ([Ca²⁺]_i) with the same efficacy of the endogenous cADPR in rat primary cortical neurons.

Keywords: Calcium mobilization; Hata’s reaction; IP3; Neuroblastoma; Phosphorylation; Primary cortical neurons; Ryanodine receptors; [Ca(2+)](i); cADPR.