Effects of valproic acid derivatives on inositol trisphosphate depletion, teratogenicity, glycogen synthase kinase-3{beta} inhibition, and viral replication: a screening approach for new bipolar disorder drugs derived from the valproic acid core structure

Abstract

ABSTRACT Inositol-1,4,5-trisphosphate (InsP 3 ) depletion has been implicated in the therapeutic action of bipolar disorder drugs, including valproic acid (VPA). It is not currently known whether the effect of VPA on InsP 3 depletion is related to the deleterious effects of teratogenicity or elevated viral replication, or if it occurs via putative inhibitory effects on glycogen synthase kinase-3␤ (GSK-3␤). In addition, the structural requirements of VPA-related compounds to cause InsP 3 depletion are unknown. In the current study, we selected a set of 10 VPA congeners to examine their effects on InsP 3 depletion, in vivo teratogenic potency, HIV replication, and GSK-3␤ activity in vitro. We found four compounds that function to deplete InsP 3 in the model eukaryote Dictyostelium discoideum, and these drugs all cause growth-cone enlargement in mammalian primary neurons, consistent with the effect of InsP 3 depletion. No relationship was found between InsP 3 depletion and teratogenic or elevated viral replication effects, and none of the VPA congeners were found to affect GSK-3␤ activity. Structural requirements of VPA congers to maintain InsP 3 depletion efficacy greater than that of lithium are a carboxylic-acid function without dependence on side-chain length, branching, or saturation. Noteworthy is the enantiomeric differentiation if a chiral center exists, suggesting that InsP 3 depletion is mediated by a stereoselective mode of action. Thus, the effect of InsP 3 depletion can be separated from that of teratogenic potency and elevated viral replication effect. We have used this to identify two VPA derivatives that share the common InsP 3 -depleting action of VPA, lithium and carbamazepine, but do not show the side effects of VPA, thus providing promising novel candidates for bipolar disorder treatment