Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter.
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.
Simoni
Daniele
D
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. smd@dns.unife.it
Rossi
Marcello
M
Bertolasi
Valerio
V
Roberti
Marinella
M
Pizzirani
Daniela
D
Rondanin
Riccardo
R
Baruchello
Riccardo
R
Invidiata
Francesco Paolo
FP
Tolomeo
Manlio
M
Grimaudo
Stefania
S
Merighi
Stefania
S
Varani
Katia
K
Gessi
Stefania
S
Borea
Pier Andrea
PA
Marino
Silvia
S
Cavallini
Sabrina
S
Bianchi
Clementina
C
Siniscalchi
Anna
A
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
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