Major depression disorder is significant health problem with 10-20% of all adults suffering from this disease. Monoamine therapies have so far been the most successful approach for treating depression. Although dopaminergic inhibition has been strongly associated with depression evidenced by preclinical and clinical studies, currently available treatment involves inhibition of serotonergic and noradrenergic system but not dopaminergic neurotransmission. Recently, triple reuptake inhibitors (TUI), which inhibits uptake of all three neurotransmitters, have recently been implicated in new generation of potent antidepressants. Preclinical studies indicate that a drug inhibiting the uptake of all three of these neurotransmitters could produce a more rapid onset of action and should possess greater efficacy compared to traditional antidepressants and also address anhedonia due to additional dopaminergic activity. In our on-going SAR studies to discover new molecules for development of novel TUIs, we have designed and synthesized several asymmetric di- and tri-substituted pyran derivatives. Uptake inhibition studies with all three monoamine transporters indicated variety of activities depending upon the nature of substitutions either on the pyran ring or on the N-benzyl moiety. SAR studies indicate the compound D-485  showed triple reuptake inhibitory (TUI) activity profile, as these molecules exhibited potent uptake inhibition for all the monoamine transporters ((Ki of 234.0 nM, 2.68 nM, and 33.6 nM for DAT, SERT, and NET respectively). Synthesis and SAR studies will be presented. This work is supported by National Institute of Mental Health/ National Institute of Health MH084888 (AKD).

Further structure activity relationship studies of 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol and its analogs: Identification of novel triple uptake inhibitors as new generation antidepressants

243rd National Meeting (2012)

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