Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter

Stefania Grimaudo, Matteo Rossi, Marcello Rossi, Daniela Pizzirani, Riccardo Baruchello, Riccardo Rondanin, Stefania Merighi, Stefania Gessi, Valerio Bertolasi, Pier Andrea Borea, Anna Siniscalchi, Daniele Simoni, Katia Varani, Silvia Marino, Marinella Roberti, Clementina Bianchi, Sabrina Cavallini, Francesco Invidiata

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Abstract

A series of 6α- and 6β-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6β-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6α-methoxy-3-(4′,4″- difluorodiphenylmethoxy)-tropane (5g) was the most potent compound. It has been found that modifications at the 6-position of benztropine might reduce the DAT binding affinity, maintaining otherwise a significant dopamine uptake inhibitory activity. A reinvestigation of the absolute configuration of 6β-methoxytropinone proved the 6R configuration for the (+)-enantiomer.
Lingua originaleEnglish
pagine (da-a)3337-3343
Numero di pagine7
RivistaJournal of Medicinal Chemistry
Volume48
Stato di pubblicazionePublished - 2005

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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Grimaudo, S., Rossi, M., Rossi, M., Pizzirani, D., Baruchello, R., Rondanin, R., Merighi, S., Gessi, S., Bertolasi, V., Borea, P. A., Siniscalchi, A., Simoni, D., Varani, K., Marino, S., Roberti, M., Bianchi, C., Cavallini, S., & Invidiata, F. (2005). Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter. Journal of Medicinal Chemistry, 48, 3337-3343.