Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs.
New methods for the synthesis of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (6a, RTI-55) or to an N-protected derivative of 6a followed by N-demethylation or removal of the protecting group. Some analogs were prepared by catalytic reduction of the alkene and alkene analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4 were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters. 3 beta-(4'-Isopropenyl- and 4'-cis-propenylphenyl)nortropane-2 beta-carboxylic acid methyl esters (3b,d), which possessed IC50 values of 0.6 and 1.15 nM, respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50 ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE transporter. Since interaction with the serotonin transporter may modulate the pharmacological effects resulting from binding to the dopamine transporter, 3 beta-(4'-isopropenylphenyl)tropane-2 beta-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA transporters but low affinity at the NE transporter may be useful for studying this interaction.
Blough
B E
BE
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Abraham
P
P
Lewin
A H
AH
Kuhar
M J
MJ
Boja
J W
JW
Carroll
F I
FI
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D009662:Nortropanes / Q000138:chemical synthesis* / Q000378:metabolism; D017374:Paroxetine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000378:metabolism
D002352:Carrier Proteins; D003042:Cocaine; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D009662:Nortropanes; D017374:Paroxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014326:Tropanes; C101731:3-(4'-isopropenylphenyl)nortropane-2-carboxylic acid methyl ester; C101730:3-(4'-isopropenylphenyl)tropane-2-carboxylic acid methyl ester; C101732:3-(4'-propenylphenyl)nortropane-2-carboxylic methyl ester; C493232:Slc6a4 protein, rat; C011386:nisoxetine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester