More than two million American adults, or approximately one percent of the population 18 years or older, suffer from
bipolar disorder. Current treatments include the so-called "mood stabilizers,"
lithium and
valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including
weight gain. Based upon continued efforts to understand the molecular target for
lithium, it now appears that specific inhibitors of the
enzyme glycogen synthase kinase-3beta (GSK-3beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with
bipolar disorder as well as certain
neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the
GSK-3 enzyme suggest the possible use of such inhibitors as
neuroprotective agents. In fact, neuroprotection may contribute to the treatment of
mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective
GSK-3beta inhibitors. The best
ligand in this series (having a Ki value of 4.6 nM against
GSK-3beta) was studied in a novel mouse model of
mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a
GSK-3beta inhibitor in this mouse model of
mania. Selective brain penetrable
GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted
kinase in both physiological and pathophysiological events.