Effects of two-carbon bridge region methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter.
6-Methoxylated and 8-oxygenated benztropines were prepared and evaluated for their DAT and SERT activity (binding and uptake inhibition). Methoxylation at the two-carbon bridge of benztropine produced a novel class of potent and selective DAT ligands. An interesting enantioselectivity was also observed for this new class of chiral benztropines. The inactivity of the 8-oxygenated analogues seems to point out that, unlike cocaine and its analogues, interactions of benztropine ligands with DAT may be strongly governed by the nitrogen atom.
Simoni
D
D
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy. smd@dns.unife.it
Roberti
M
M
Rondanin
R
R
Baruchello
R
R
Rossi
M
M
Invidiata
F P
FP
Merighi
S
S
Varani
K
K
Gessi
S
S
Borea
P A
PA
Marino
S
S
Cavallini
S
S
Bianchi
C
C
Siniscalchi
A
A
D001590:Benztropine / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008968:Molecular Conformation; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D001590:Benztropine