Issue 19, 2004

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

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

Article information

Article type
Paper
Submitted
19 Apr 2004
Accepted
30 Jul 2004
First published
06 Sep 2004

Org. Biomol. Chem., 2004,2, 2861-2869

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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