Synthesis and ligand binding of tropane ring analogues of paroxetine
(3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]propane (4). The data for inhibition of [H-3]paroxetine binding show that (1R)-2 beta,3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [H-3]WIN-35,428 binding were not the (1R)-2 beta,3 beta-isomers but rather (1R)-2 beta,3 alpha-4c and (1S)-2 beta,3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.
Keverline-Frantz, K. I., Boja, J. W., Kuhar, M. J., Abraham, P., Burgess, J., Lewin, A., & Carroll, F. (1998). Synthesis and ligand binding of tropane ring analogues of paroxetine. Journal of Medicinal Chemistry, 41(2), 247-257.