Unipolar depression, caused by an imbalance of monoamine neurotransmitters in brain, is ranked as the most prevalent of all somatic and psychiatric illness. It is estimated that about 40 % of patients remains refractory to treatment thereby limiting the use of current anti-depressant drugs. Moreover, because of relapse and unwanted side effects of existing drugs there is an unmet need to discover novel agents for the treatment of this devastating mental disorder. Current treatment aims at alleviating extraneuronal concentration of serotonin (5-HT) and norepinephrine (NE) but do not include dopaminergic element, which is also implicated in depression, into the therapy. Tremendous efforts are underway to inhibit all the three neurotransmitters with an aim to discover drugs with broader spectrum and faster onset of action. In our pursuit of effective drugs to treat depression, we have developed novel di- and tri-substituted pyran derivatives with balanced inhibitory activities at all the three transmitters that demonstrated anti-depressant effect in in vivo animal models. In this study, we report a triple monoamine uptake inhibitor (TUI) pharmacophore model that revealed a distinct 'folded' conformation and suggests features common to inhibitors that exhibited a TUI profile. Furthermore, the distances between the benzhydryl moiety and the N-benzyl group as well as the orientation of the secondary nitrogen were also important for TUI activity. We have validated our findings by synthesizing and testing novel asymmetric pyran analogs. Furthermore, a series of asymmetric tetrahydrofuran derivatives that fitted the pharmacophore model were synthesized and evaluated as a novel class of TUI as anti-depressant agents. Supported by MH84888 (AD).

Development of pharmacophore model and asymmetric synthesis of novel tetrahydrofuran derivatives enroute to triple reuptake inhibitors as anti-depressant agents

248th National Meeting (2014)

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