Synthesis and transporter binding properties of 2,3-diphenyltropane stereoisomers. Comparison to 3beta-phenyltropane-2beta-carboxylic acid esters.
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.
Chang
A C
AC
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Burgess
J P
JP
Mascarella
S W
SW
Abraham
P
P
Kuhar
M J
MJ
Carroll
F I
FI
D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D012701:Serotonin; C021278:troparil; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine