Journal of Medicinal Chemistry 1997-04-11

Synthesis and transporter binding properties of 2,3-diphenyltropane stereoisomers. Comparison to 3beta-phenyltropane-2beta-carboxylic acid esters.

A C Chang, J P Burgess, S W Mascarella, P Abraham, M J Kuhar, F I Carroll

Index: J. Med. Chem. 40(8) , 1247-51, (1997)

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Abstract

2beta,3beta-Diphenyl-(5), 2alpha,3alpha-diphenyl-(6), and 2alpha,3beta-diphenyltropane (3) as well as 2,3-diphenyltrop-2-ene (4) were prepared in racemic form and assayed for inhibition of radioligand binding at the dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters. Among all three transporters, compounds 4-6 bound the DA transporter with the highest affinity. The 2beta,3beta-diphenyltropane (5) bound the DA transporter with an IC50 value (28 nM) almost identical to that of 3beta-phenyltropane-2beta-carboxylic acid methyl ester (WIN 35,065-2) and has much greater selectivity relative to binding to the serotonin transporter. A comparison of the radioligand data from this study to radioligand data obtained on other WIN 35,065-2 analogs suggests that hydrophobicity of the C-2 substituent of some analogs of the WIN 35,065-2 class may be an important contributing factor to binding at the DA transporter.