Further structure–activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

Abstract

The synthesis and structure-activity relationships of 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives were investigated at the dopamine transporter(DAT), the serotonin transporter (SERT) and norepinephrine transporter (NET). The rigid ethylidenyl-8-azabicyclic[3.2.1]octane skeleton imparted modestly stereoselective binding and uptake inhibition at the DAT. Additional structure-activity studies provided a transporter affinity profile that was reminiscent of the structure-activity of GBR 12909. From these studies, the 8-cyclopropylmethyl group has been identified as a unique moiety that imparts high SERT/DAT selectivity. In this study the 8-cyclopropylmethyl derivative 22e (DAT Ki of 4.0 nM) was among the most potent compounds of the series at the DAT and was the most DAT selective ligand of the series (SERT/DAT:1060). Similarly, the 8-chlorobenzyl derivative 22g (DAT Ki of 3.9 nM) was found to be highly selective for the DAT over the NET (NET/DAT: 1358).

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters

“…18 The monoamine transporter binding affinities of the 3-arylmethoxy-3-aryl-azetidines ( 6 ) were generally selective for the SERT over the DAT exhibiting nanomolar affinity for the SERT and micromolar affinity for the DAT. The dichloro substituted congeners 6e ( K i = 3.5 nM) and 6h ( K i = 2.9 nM) were the most potent of the azetidines at SERT.…”