3-ARYL-2-(3'-SUBSTITUTED-1',2',4'-OXADIAZOL-5'-YL)TROPANE ANALOGS OF COCAINE - AFFINITIES AT THE COCAINE BINDING-SITE AT THE DOPAMINE, SEROTONIN, AND NOREPINEPHRINE TRANSPORTERS

Previous studies have shown that 3beta-(substituted phenyl)tropan-2beta-carboxylic acid esters possess high affinity for the cocaine binding site on the dopamine transporter both in vitro and in vivo and inhibit dopamine uptake in vitro. Since 1,2,4-oxadiazoles are excellent bioisosteres of ester groups, we have prepared several 3beta-(substituted phenyl)-2beta-(3-substituted 1',2',4'-oxadiazol-5'-yl)tropanes (5b-h) and all four stereoisomers of (1R,5S)-3 phenyl-2-(3-methyl-1',2',4'-oxadiazol-5'-yl)tropane (5a and 6-8). The 3alpha-phenyl-2alpha-(3'-methyl-1',2',4'-oxadiazole) isomer 7 was prepared from a stereoselective addition of phenyllithium to (1R,5S)-2-(3'-methyl-1',2',4'-oxadizol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene(11). The binding affinities for 5a-h and 6-8 at the dopamine, serotonin, and norepinephrine transporters were obtained. In general these bioisosteres showed potencies for the dopamine transporter similar to those of their parent esters. 3beta-(4'-Chlorophenyl)-2beta-(3'-phenyl-1',2',4'-oxadiazol-5'-yl)tropane (5d) was the most potent analogue with an IC50 of 1.62 nM. However, 3beta-(4'-chlorophenyl)-2beta-(3'-methoxyphenyl-1',2',4'-oxadiazol-5'-yl)tropane (5e) with an IC50 of 1.81 nM was the most selective analogue for the dopamine transporter showing NE/DA and 5-HT/DA ratios of 461 and 186, respectively. The cis- and trans-3alpha-phenyl-2-(3'-methyl-1',2',4'-oxadiazol-5'-yl)tropanes (7 and 8), which exist in a boat conformation, have IC50 values only slightly greater than that of the 3beta,2beta-isomer (5a) which possesses the cocaine stereochemistry.