Synthesis and Monoamine Transporter Binding Properties of 2,3-Diaryltropanes

Synthetic procedures were developed for the synthesis of 2β,3β- and 2α,3α-diaryltropanes. These compounds are analogues of the 3-aryltropane-2β-carboxylic acid methyl ester class of monoamine uptake inhibitors, where the 2β-carbomethoxy group has been replaced by an aryl group. The compounds were evaluated for inhibition of radioligand binding at the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and 5-HTT, respectively). The results showed that the replacement of the 2β-carbomethoxy group in the 3-aryltropane class with a 2β-aryl group led to compounds possessing very similar monoamine transporter binding properties. However, the 2β,3β-diaryltropanes tended to be more potent at the DAT and more selective for the DAT relative to the NET and 5-HTT. One of the most interesting compounds was 3β-(4-methylphenyl)-2β-(4-methylphenyl)tropane (3d), which showed an IC50 of 1.23 nM at the DAT with 289- and 185-fold selectivity for the DAT relative to the NET and 5-HTT. The 2α,3α-diaryltropanes were much less potent at all three transporters than 2β,3β-diaryltropanes.