Pyridine derivatives with bridgesPyridine derivatives with bridges R 0460Synthesis of Dopamine Transporter Selective 3-{2-(Diarylmethoxyethylidene)}-8-alkylaryl-8-azabicyclo[3.2.1]octanes. -The preparation of title compounds (IX) in good yields and the determination of their binding affinities at dopamine and serotonine transporters are reported. Compounds (IXa) and (IXb) showed highest potency among the prepared compounds. -(BRADLEY, A. L.; IZENWASSER, S.; WADE, D.; CARARAS, S.; TRUDELL*, M. L.; Bioorg. Med. Chem. Lett. 13 (2003) 4, 629-632; Dep. Chem., Univ. New Orleans, New Orleans, LA 70148, USA; Eng.) -M. Schroeter 25-161
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).
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