Synthesis and monoamine transporter binding of 2-(diarylmethoxymethyl)-3 beta-aryltropane derivatives

3 beta-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively, the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor selectivity over SERT. These SAR studies provide further evidence for the varied binding requirements of structurally diverse tropane-based ligands and support future studies to elucidate DAT binding requirements in relation to cocaine-like behavioral endpoints.