Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter
- Authors: SIMONI D; ROSSI M; BERTOLASI V; ROBERTI M; PIZZIRANI D; RONDANIN R; BARUCHELLO R; INVIDIATA FP; TOLOMEO M; GRIMAUDO S; MERIGHI S; VARANI K; GESSI S; BOREA PA; MARINO S; CAVALLINI S; BIANCHI C; SINISCALCHI A
- Publication year: 2005
- Type: Articolo in rivista (Articolo in rivista)
- Key words: Dopamine Plasma Membrane Transport Proteins; Cocaine; triple reuptake
- OA Link: http://hdl.handle.net/10447/14975
Abstract
A series of 6α- and 6β-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6β-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6α-methoxy-3-(4′,4″- difluorodiphenylmethoxy)-tropane (5g) was the most potent compound. It has been found that modifications at the 6-position of benztropine might reduce the DAT binding affinity, maintaining otherwise a significant dopamine uptake inhibitory activity. A reinvestigation of the absolute configuration of 6β-methoxytropinone proved the 6R configuration for the (+)-enantiomer.