title: 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 K(i) 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 K(i) of 3.9 nM) was found to be highly selective for the DAT over the NET (NET/DAT: 1358).
authors: Department of Chemistry, University of New Orleans, New Orleans, 2000 Lakeshore Drive, LA 70148, USA.
authors: Shaine A
authors: SA
authors: Cararas
authors: Sari
authors: S
authors: Izenwasser
authors: Dean
authors: D
authors: Wade
authors: Amy
authors: A
authors: Housman
authors: Abha
authors: A
authors: Verma
authors: Stacey A
authors: SA
authors: Lomenzo
authors: Mark L
authors: ML
authors: Trudell
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D009795:Octanes / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009795:Octanes; D050486:Serotonin Plasma Membrane Transport Proteins; C026728:octane