Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding, Competitive
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Brain / metabolism
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Carrier Proteins / metabolism*
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Cocaine / analogs & derivatives
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Cocaine / metabolism
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Dopamine / metabolism
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Dopamine Uptake Inhibitors
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Fluoxetine / analogs & derivatives
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Fluoxetine / metabolism
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins*
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Molecular Structure
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Nerve Tissue Proteins*
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Norepinephrine / antagonists & inhibitors
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Norepinephrine / metabolism
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Nortropanes / chemical synthesis*
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Nortropanes / metabolism
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Paroxetine / metabolism
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Radioligand Assay
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Rats
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Selective Serotonin Reuptake Inhibitors
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Serotonin / metabolism
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists / chemistry*
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Serotonin Receptor Agonists / metabolism
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Structure-Activity Relationship
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Tropanes / chemical synthesis*
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Tropanes / metabolism
Substances
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3-(4'-isopropenylphenyl)nortropane-2-carboxylic acid methyl ester
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3-(4'-isopropenylphenyl)tropane-2-carboxylic acid methyl ester
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3-(4'-propenylphenyl)nortropane-2-carboxylic methyl ester
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Carrier Proteins
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Dopamine Uptake Inhibitors
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Nortropanes
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists
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Serotonin Uptake Inhibitors
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Slc6a4 protein, rat
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Tropanes
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Fluoxetine
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nisoxetine
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Serotonin
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Paroxetine
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(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
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Cocaine
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Dopamine
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Norepinephrine