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Issue 19, 2004
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Combinatorial synthesis of benztropine libraries and their evaluation as monoamine transporter inhibitors

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Abstract

A combinatorial synthesis of benztropine analogues is presented. Radical azidonation of 3-benzyloxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3 to 3-(1-azidobenzyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 4 was used as a key step in the synthesis. This step was optimized by adding 10% DMF to the reaction. Reaction of 4 with phenyl magnesium bromide followed by Boc removal and N-methylation gave benztropine 1. Reaction of five-component Grignard reagents with 4 was used to create a two-dimensional library of 25 N-normethylbenztropine analogues. Further reaction of this library with five alkyl bromides was carried out to create a three-dimensional library containing 125 compounds. Screening of the libraries towards binding and inhibition of uptake of the human dopamine (hDAT), serotonin (hSERT) and norepinephrine transporters (hNET) was carried out. None of the synthesized compounds were found to be stronger than benztropine, and none were selective for inhibition of binding over monoamine uptake.

Graphical abstract: Combinatorial synthesis of benztropine libraries and their evaluation as monoamine transporter inhibitors

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Publication details

The article was received on 19 Apr 2004, accepted on 30 Jul 2004 and first published on 06 Sep 2004


Article type: Paper
DOI: 10.1039/B405768F
Citation: Org. Biomol. Chem., 2004,2, 2861-2869
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    Combinatorial synthesis of benztropine libraries and their evaluation as monoamine transporter inhibitors

    H. Pedersen, S. Sinning, A. Bülow, O. Wiborg, L. Falborg and M. Bols, Org. Biomol. Chem., 2004, 2, 2861
    DOI: 10.1039/B405768F

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