World-wide public health surveys point to an increased global health burden for serious psychiatric disorders, particularly depression. Indeed, by 2020 it is expected that depression may be the second most serious medical condition with respect to global disease burden. It is clear that more effective pharmacotherapies are needed in treating depressive illness. Selective ligands for the norepinephrine transporter (NET) such as desipramine are quite effective in some patient populations, but their use is often limited by side effects, particularly those thought to be mediated by their anticholinergic properties. More selective NET ligands may have considerable application in the treatment of depression. However, currently there are very few NET-selective ligands available. The studies described in this research proposal involve the synthesis and pharmacological evaluation of novel conformationally constrained tricyclic tropane analogues that are designed to be potent NET-selective inhibitors. For the best NET inhibitors identified, we will then screen them in animal models of depression. Additionally, it is reasonable that such ligands could be utilized with positron emission tomography (PET) imaging to assess changes in noradrenergic terminal fields in a variety of human conditions including depression. Thus, these ligands could be a significant addition to the clinical armamentarium available to treat and diagnose psychiatric disease. Within the context of this grant, it is our intention to follow up on our exciting preliminary findings of potent NET-selective compounds by conducting the following studies: 1. Further elaborate the biaryl and thienyl series of conformationally constrained tricyclic tropane analogues based on the SAR information already in hand; 2. Investigate certain phenylacetylene analogues that are derived from our biaryl analogues by the replacement of Ar1 with a triple bond as an aromatic ring bioisostere.; 3. Assay the inhibitory activity of all new ligands at the NET, SERT, DAT and the muscarinic receptor; 4. Scale up the synthesis of the most drug-like NET-inhibitors and study these in animal models of depression. Key words: depression, norepinephrine transporter (NET) inhibitors, conformationally constrained tricyclic tropanes, pharmacotherapy, PET imaging, chemical synthesis, behavioral testing.
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