Synthesis and Pharmacology of 6-Substituted Benztropines: Discovery of Novel Dopamine Uptake Inhibitors Possessing Low Binding Affinity to the Dopamine Transporter

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.