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 mu M) than cocaine and 2 beta-(methoxycarbonyl)-3 beta-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3 alpha-phenyl isomers (6c, 6d) were more potent than the 3 beta-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2. I]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2 beta-(methoxycarbonyl)-3-phenyltropanes.