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

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 beta (GSK- 3 beta). 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 beta 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 beta 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.