Synthesis and dopamine transporter affinity of the four stereoisomers of (±)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane

All four stereoisomers of (±)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7- azabicyclo[2.2.1]heptane were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured in rat caudate-putamen tissue and found to be 100-3000-fold less potent (K(i) = 5- 96 μM) than cocaine and 2β-(methoxycarbonyl)-3β-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3α-phenyl isomers (6c, 6d) were more potent than the 3β-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2.1]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2β(methoxycarbonyl)-3-phenyltropanes.