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ORIGINAL ARTICLE

Effects of Valproic Acid Derivatives on Inositol Trisphosphate Depletion, Teratogenicity, Glycogen Synthase Kinase-3 Inhibition, and Viral Replication: A Screening Approach for New Bipolar Disorder Drugs Derived from the Valproic Acid Core Structure

Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, London, United Kingdom (B.J.E., N.H.C.); Wohl Virion Centre, Department of Immunology and Molecular Pathology (G.J.T., L.M.J.Y.), Medical Research Council Laboratory of Molecular Cell Biology (W.J.R., A.J.H.), and Department of Biology and Wolfson Institute for Biomedical Research (K.A., R.S.B.W.), University College London, London, United Kingdom; and Institute for Food Toxicology and Chemical Analysis, Centre of Systemic Neuroscience, School of Veterinary Medicine Hanover, Hanover, Germany (D.E., H.N.)

Abstract

Inositol-1,4,5-trisphosphate (InsP₃) 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 InsP₃ 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 InsP₃ depletion are unknown. In the current study, we selected a set of 10 VPA congeners to examine their effects on InsP₃ depletion, in vivo teratogenic potency, HIV replication, and GSK-3 activity in vitro. We found four compounds that function to deplete InsP₃ in the model eukaryote Dictyostelium discoideum, and these drugs all cause growth-cone enlargement in mammalian primary neurons, consistent with the effect of InsP₃ depletion. No relationship was found between InsP₃ 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 InsP₃ 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 InsP₃ depletion is mediated by a stereoselective mode of action. Thus, the effect of InsP₃ 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 InsP₃-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.

Address correspondence to: Dr. R. S. B. Williams, Department of Biology and Wolfson Institute for Biomedical Research, University College London, London, WC1 E6BT, United Kingdom. E-mail: robin.williams{at}ucl.ac.uk

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