title: Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter.
abstract: A series of 6alpha- and 6beta-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6beta-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6alpha-methoxy-3-(4',4' '-difluorodiphenylmethoxy)tropane (5 g) 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 6beta-methoxytropinone proved the 6R configuration for the (+)-enantiomer.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. smd@dns.unife.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
authors.forename: Marcello
authors.initials: M
authors.lastname: Rossi
authors.forename: Valerio
authors.initials: V
authors.lastname: Bertolasi
authors.forename: Marinella
authors.initials: M
authors.lastname: Roberti
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rondanin
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baruchello
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Invidiata
authors.forename: Manlio
authors.initials: M
authors.lastname: Tolomeo
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cavallini
authors.forename: Clementina
authors.initials: C
authors.lastname: Bianchi
authors.forename: Anna
authors.initials: A
authors.lastname: Siniscalchi
mesh_terms: D000818:Animals; D001590:Benztropine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008968:Molecular Conformation; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C500849:6-methoxy-3-(4',4''-difluorodiphenylmethoxy)tropane; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; D014326:Tropanes; D001590:Benztropine; D004298:Dopamine