Synthesis and biological evaluation of tropane-like 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl) piperazine (GBR 12909) analogues

We have prepared azabicyclo [3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopami ne reuptake. Within the series, 3-{2-[bis-(4-fluorophenyl)methoxyl ethylide ne}-8-methyl-8-azabicyclo [3.2.1] octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo [3. 2.1] (bridged piperidine) series of compounds differ from the well-known be nztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Int erestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Re placing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3-10-fold increase in binding affinity for the dopamine transporter. Howeve r, those compounds lost selectivity for the dopamine transporter over the s erotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3 alpha -substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3 alpha -substituted tropanes had lower affinity and less selectivity than the comp arable unsaturated ligands.