Synthesis and monoamine transporter binding properties of 3beta-(3',4'-disubstituted phenyl)tropane-2beta-carboxylic acid methyl esters.

doi:10.1021/JM040185A

Paper

Synthesis and monoamine transporter binding properties of 3beta-(3',4'-disubstituted phenyl)tropane-2beta-carboxylic acid methyl esters.

Published Mar 18, 2005 · F. Carroll, B. Blough, Z. Nie

Journal of medicinal chemistry

Q1 SJR score

15

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0

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Abstract

3beta-(3'-Methyl-4'-chlorophenyl)tropane-2-carboxylic acid methyl ester (3b, RTI-112) is a 3-phenyltropane analogue that has high affinity for both the dopamine and serotonin transporters (DAT and 5-HTT, respectively). Compound 3b shows significant reduction of cocaine self-administration in rhesus monkeys, yet fails to maintain robust drug self-administration. PET studies revealed that unlike more DAT selective analogues such as GBR 12 909 and 3-(4-chlorophenyl)tropane-2-carboxylic acid phenyl ester (RTI-113), 3b shows no detectible DAT occupancy when dosed at its ED(50) for reduction of cocaine self-administration. In contrast, it highly occupies the 5-HTT at this dose. In this study, we report the synthesis and monoamine transporter binding potency of several new 3-(3',4'-disubstituted phenyl)tropane-2-carboxylic acid methyl esters (3c-k), which have binding properties very similar to 3b. With the exception of the 3',4'-dimethyl analogue 3k, all of the compounds possess subnanomolar IC(50) and K(i) values at the DAT and 5-HTT, respectively. The 3'-chloro-4'-bromo analogue 3e (IC(50) = 0.12 nM) and the 3'-bromo-4'-iodo analogue 3i (K(i) = 0.14 nM) are the most potent analogues at the DAT and 5-HTT, respectively. These compounds will be useful to further characterize the highly interesting behavioral profile of 3b.

Non-RCT

Animal Study

Study Snapshot

New 3-(3',4'-disubstituted phenyl)tropane-2-carboxylic acid methyl esters (3c-k) show similar binding properties to 3b, with the most potent binding at the dopamine and serotonin transporters.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis and monoamine transporter binding properties of 3beta-(3',4'-disubstituted phenyl)tropane-2beta-carboxylic acid methyl esters.

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References

Citations

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