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.
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