Premium
Synthesis of 3,7‐Disubstituted Imipramines by Palladium‐Catalysed Amination/Cyclisation and Evaluation of Their Inhibition of Monoamine Transporters
Author(s) -
Christensen Helle,
SchjøthEskesen Christina,
Jensen Marie,
Sinning Steffen,
Jensen Henrik H.
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201100885
Subject(s) - imipramine , chemistry , selectivity , tricyclic , serotonin transporter , transporter , amination , reductive amination , stereochemistry , serotonin , organic chemistry , biochemistry , receptor , catalysis , medicine , alternative medicine , pathology , gene
We describe a novel approach for the synthesis of a series of 3,7‐difunctionalised symmetric and unsymmetrical analogues of the tricyclic antidepressant (TCA) imipramine, which uses a key palladium‐catalysed amination/cyclisation of an ester‐functionalised dibromide. Of the ester, methyl, hydroxymethyl and methoxymethyl disubstituted compounds prepared, 3,7‐dimethyl‐imipramine was found to be the most potent against the human serotonin transporter (hSERT). The inhibitory potency of 3,7‐dimethyl imipramine was found to be at least as high as the parent imipramine. This novel TCA also exhibits an increased selectivity (relative to imipramine) in binding to hSERT versus the human norepinephrine transporter (hNET). Even higher selectivity could be obtained with 3,7‐dihydroxymethyl imipramine, which was found to be 167‐fold more selective for hSERT over hNET, representative of a 120‐fold gain in selectivity relative to the parent imipramine. These results further validate our previous model for the binding of imipramine and high‐affinity analogues of imipramine to the central binding site of hSERT.