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.

Isomerisation and configurational assignment of 2-alkyltropane and 2-alkylgranatane derived hydrazones

“…Final R and R w were 0.0472 and 0.1290, respectively. 14 3,5-dinitrobenzoate. The crystals of 2-benzyltropinone 3,5-dinitrobenzoate for XRD analysis were obtained as a yellow solid, mp 176e178 C, by crystallization of a mixture of the ketone (0.050 g, 0.218 mmol) and 3,5-dinitrobenzoic acid (0.046 g, 0.218 mmol) from isopropanol (10 mL) at rt.…”

Determination of the N-invertomer stereochemistry in N-substituted nortropanones and norgranatanones using computational and NMR methods

“…Tropane (8-methyl-8-azabicyclo-[3.2.1]octane) and granatane (9-azabicyclo[3.3.1]nonane) are bicyclic structures [1] found in numerous bioactive naturally occurring and synthetic compounds [2,3]. Tropinone (1, R = Me) and granatanone (also known as pseudopelletierine, pseudopelletrierin or N-methylgranatanone 2, R = Me) [4] are simple and are among the best-known representatives of these groups of compounds (Fig.…”

Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

“…Earlier SAR studies had shown that removal of the proximal nitrogen in 1,2-dialkylpiperazine analogs did not have a significant effect on DAT affinity [51,52]. However, this change reduces chances of binding to the piperazine site [52].…”

“…The compound showing the highest DAT affinity in these flexible analogs was the N-butyl-4',4'-dichloro analog D28, which had an IC 50 of 12.5 nM [85]. Using combinatorial methods, a library of benztropine analogs having structures D29 were synthesized where R and R' were varied [51]. None of the analogs possessed DAT affinity higher than that of benztropine (D1).…”