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
Fi. Carroll et al., 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, Journal of medicinal chemistry, 36(20), 1993, pp. 2886-2890
Previous studies have shown that 3beta-(substituted phenyl)tropan-2bet
a-carboxylic acid esters possess high affinity for the cocaine binding
site on the dopamine transporter both in vitro and in vivo and inhibi
t dopamine uptake in vitro. Since 1,2,4-oxadiazoles are excellent bioi
sosteres 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 henyl-2-(3-methyl-1',2',4'-oxa
diazol-5'-yl)tropane (5a and 6-8). The lpha-phenyl-2alpha-(3'-methyl-1
',2',4'-oxadiazole) isomer 7 was prepared from a stereoselective addit
ion of phenyllithium to l-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, serotoni
n, and norepinephrine transporters were obtained. In general these bio
isosteres showed potencies for the dopamine transporter similar to tho
se of their parent esters. -2beta-(3'-phenyl-1',2',4'-oxadiazol-5'-yl)
tropane (5d) was the most potent analogue with an IC50 of 1.62 nM. How
ever, (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 trans
porter showing NE/DA and 5-HT/DA ratios of 461 and 186, respectively.
The cis- and nyl-2-(3'-methyl-1',2',4'-oxadiazol-5'-yl)tropanes (7 and
8), which exist in a boat conformation, have IC50 values only slightl
y greater than that of the 3beta,2beta-isomer (5a) which possesses the
cocaine stereochemistry.