SYNTHESIS AND DOPAMINE TRANSPORTER AFFINITY OF THE 4 STEREOISOMERS OF(+ NYL)-7-METHYL-3-PHENYL-7-AZABICYCLO[2.2.1]HEPTANE/

All four stereoisomers of onyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]h eptane 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 caudat e-putamen tissue and found, to be 100-3000;fold less potent (K-i = 5-9 6 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 mo deling studies revealed that the rigid 7-azabicyclo[2.2. I]heptane der ivatives possess molecular topologies which are significantly differen t than the molecular topologies of the 2 beta-(methoxycarbonyl)-3-phen yltropanes.