Depression and cocaine addiction are serious problems with which society is currently burdened. Both disorders are believed to be related to monoaminergic activity in-vivo and as such, drugs such as venlafaxine that inhibit reuptake of monoamines such as serotonin (SER), dopamine (DA) and norepinephrine (NE) are of interest for treatment. One enantiomer of venlafaxine (VFX), a racemic drug, has been shown to be a very potent SER and NE reuptake inhibitor, while the other enantiomer is specific only for SER. This study proposes to develop a short, enantioselective method for synthesis of a variety of VFX analogues and to test these analogues for selectivity in SER, DA and NE transporter binding. The methodology to be used involves a rhodium catalyzed, tandem C-H insertion/Cope rearrangement reaction that has been previously developed to rapidly assemble the molecular framework in enantiopure form. The methodology will then be adapted to a system with the catalyst suspended on solid phase for rapid library development. The data collected from biological testing of these analogues should provide insight into the interplay of SER, NE, and DA levels in-vivo and their role in depression and cocaine addiction.
| Manning, James R; Sexton, Tammy; Childers, Steven R et al. (2009) 1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors. Bioorg Med Chem Lett 19:58-61 |
| Manning, James R; Davies, Huw M L (2008) Efficient route to 4H-1,3-oxazines through ring expansion of isoxazoles by rhodium carbenoids. Tetrahedron 64:6901-6908 |
| Manning, James R; Davies, Huw M L (2008) One-pot synthesis of highly functionalized pyridines via a rhodium carbenoid induced ring expansion of isoxazoles. J Am Chem Soc 130:8602-3 |
