Synthesis and Dopamine Transporter Affinity of 2-(Methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane Derivatives

A series of 9-methyl-3β-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (K i) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (K i = 2−14 μM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)−C(7)] of cocaine and cocaine-like compounds.