More than 2 million American adults, or about 1 percent of the population age 18 and older in any given year, have 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-3b (GSK-3b) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest a potential use of such inhibitors as neuroprotective agents. Neuroprotection may further contribute to the therapeutic efficacy of mood disorder drugs. A number of synthetic GSK-3 inhibitors are now currently available but many of these have not been fully characterized in a battery of biological tests, nor are they readily available to academic researchers. These compounds are largely ATP competitive inhibitors whose kinase activity has been determined in vitro; in many cases their true kinase selectivity profiles and their in vivo action including possible side-effects remain to be established. Clearly, novel, selective and safe GSK-3 inhibitors are needed as both pharmacological tools and as therapeutics for application to a variety of CNS disorders, including various bipolar disorders, but also Parkinson's disease, and Alzheimer's disease to name a few. To date, we have already identified some nM potency GSK-3 inhibitors that emerged from our SAR studies of staurosporine. Moreover, we have found that some of these ligands are able to exert a neuroprotective action in vitro. We anticipate that further research efforts may well lead to compounds that can be advanced to the clinic. To achieve this goal, our aims are as follow:
AIM 1 : Further expand and improve upon the potent GSK-3 inhibitors we have already identified using rational drug design principles; the selection of new ligands for synthesis will be aided by the use of in silico docking methods and these compounds then synthesized in mg to gram amounts;
AIM 2 : All newly synthesized ligands will be tested in the kinase assays to evaluate their selectivity and potency to inhibit the GSK-3 isoforms (both a and b). For the best compounds (Kj values < 25 nM), profile them against a limited number of related kinases, namely AKT1/PKBa, CDK2/cyclin E, CDK3/cyclin E, CDK5/p25, and ICK to obtain some measure of kinase selectivity; further characterize selective ligands for in vitro effects by examining their neuroprotective action in cell culture experiments;
AIM 3 : Examine the effects of the best GSK-3 inhibitors (Ki < 25 nM with a selectivity of at least 10-fold against other kinases and showing a neuroprotective action in the low micromolar range) for their ability to exert both an antidepressant action as well as anti-manic effects in animal models;
this aim will be carried out by our behavioral collaborators at PsychoGenics Inc. using their patented SmartCube technology. ? ? ?
