3-Aryl-2-(3'-substituted-1',2',4'-oxadiazol-5'-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters

Abstract

Previous studies have shown that 3 beta-(substituted phenyl)tropan-2 beta-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 3 beta-(substituted phenyl)-2 beta-(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 3 alpha-phenyl-2-alpha-(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'-oxadiazol-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. 3 beta-(4'-Chlorophenyl)-2 beta-(3'-phenyl-1',2',4'-oxadiazol-5'-yl)tropane (5d) was the most potent analogue with an IC50 of 1.62nM. However, 3 beta-(4'-chlorophenyl)-2 beta-(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-3 alpha-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 3 beta,2 beta-isomer (5a) which possesses the cocaine stereochemistry