Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives

Abstract

A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3α derivatives were found to be the most potent compounds with the 3α-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki=5nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki=12nM) was slightly less potent than the 3α-analogue, while the 3β-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki=78nM) exhibited only modest affinity for the dopamine transporter. Only the 3α-analogue 15b (SERT/DAT=48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure–activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.