• Journal Article

Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers

Citation

Carroll, F., Runyon, S., Abraham, P., Navarro, H., Kuhar, M. J., Pollard, G. T., & Howard, J. L. (2004). Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers. Journal of Medicinal Chemistry, 47(25), 6401-6409.

Abstract

The monoamine transporter binding properties, gross behavior, and locomotor activity effects in mice and drug discrimination results in cocaine-trained rats of the 2beta3beta-, 2beta,3alpha-, 2alpha-,3beta-, and 2alpha-,3alpha-isomers of several 3-(4-substituted-phenyl)tropane carboxylic acid methyl esters were compared (2a-f, 3a-f, 4a-f, and 5b,c). The 2beta,3beta-isomer showed the highest affinity for the dopamine transporter (DAT), and the 2beta,3alpha-isomer showed the next highest affinity. The order of potency for the 2beta,3beta-isomer is 4'-chloro (2c) = 4'-iodo (2e) > 4'-bromo (2d) = 4'-methyl (2f) > 4'-fluoro (2b) > 4'-hydrogen (2a). In the case of the 2beta,3alpha-isomer, the order of affinity was 4'-bromo (3d) > 4'-iodo (3e) = 4'- chloro (3c) > 4'-methyl (3f) > 4'-fluoro (3b) > 4'-hydrogen (3a). The 4'-hydrogen, 4'-fluoro, and 4'-methyl 2alpha,3beta-isomers, 4a, 4b, and 4f, had the lowest affinity for the DAY While most of the compounds showed their highest affinity at the DAT, none were selective relative to the other two monoamine transporters. In general, the 2alpha,3alpha- and 2alpha,3beta-isomers were more toxic (death and convulsions) than the 2beta,3beta- and 2beta,3alpha-isomers. With the exception of the 2(x,3a-isomers, all compounds produced the locomotor activity stimulation typical of dopaminergic drugs. The ED50 ranges for the 2beta,3beta- (2a-f), 2beta,3alpha- (3a-f), and 2alpha,3alpha-isomers (4a-f) in the locomotor assay were 0.1-1.2, 6.6-21.8, and 2.4-11.7 mg/kg, respectively. With the exception of the 2a,3a-isomer, all compounds generalized to cocaine. The 2beta,3beta-isomers were at least 10-fold more potent than cocaine and the other three sets of isomers in this test