Synthesis and monoamine transporter binding properties of 3 beta-(3 ',4 '-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters
Carroll, F., Blough, B., Nie, Z., Kuhar, M. J., Howell, L. L., & Navarro, H. (2005). Synthesis and monoamine transporter binding properties of 3 beta-(3 ',4 '-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters. Journal of Medicinal Chemistry, 48(8), 2767-2771.
3 beta-(3'-Methyl-4'-chlorophenyl)tropane-2-carboxylic acid methyl ester (3b, RTI-112) is a 3-phenyltropane analogue that has high affinity for both the dopamine and serotonin transporters (DAT and 5-HTT, respectively). Compound 3b shows significant reduction of cocaine self-administration in rhesus monkeys, yet fails to maintain robust drug self-administration. PET studies revealed that unlike more DAT selective analogues such as GBR 12 909 and 3-(4-chlorophenyl)tropane-2-carboxylic acid phenyl ester (RTI-113), 3b shows no detectible DAT occupancy when dosed at its ED50 for reduction of cocaine self-administration. In contrast, it highly occupies the 5-HTT at this dose. In this study, we report the synthesis and monoamine transporter binding potency of several new 3-(3',4'-disubstituted phenyl)tropane-2-carboxylic acid methyl esters (3c-k), which have binding properties very similar to 3b. With the exception of the 3',4'-dimethyl analogue 3k, all of the compounds possess subnanomolar IC50 and K-i values at the DAT and 5-HTT, respectively. The 3'-chloro-4'-bromo analogue 3e (IC50 = 0.12 nM) and the 3'-bromo-4'-iodo analogue 3i (K-i = 0.14 nM) are the most potent analogues at the DAT and 5-HTT, respectively. These compounds will be useful to further characterize the highly interesting behavioral profile of 3b