An extended study of dimeric phenyl tropanes.
A series of dimeric phenyl tropanes consisting of two molecules of 4-chloro, 4-iodo or 4-(3-thiopheno)-phenyl tropane tethered together at the carboxylic acid moiety by a diamine or diol linker were prepared. The diamines used were a variety of linear, cyclic and aromatic diamines, while the diol tethered compounds were prepared by 'click' chemistry and contained a triazole in the linker. The new compounds were tested for binding to hDAT, hSERT and hNET. Amide linked chlorophenyl tropanes with an aromatic linker was found to be potent and selective DAT inhibitors with the best K(i) value for hDAT being 6nM. The ester linked halophenyl tropanes were more potent but displayed little selectivity in inhibition of monoamine transporter binding. Among the studied compounds an ester linker of 10 atoms between the tropane moieties gave the highest affinity. One monomeric phenyl tropane was made for comparison and was found to be less potent than the dimeric counterparts towards SERT and NET but remain highly active against DAT. Dimeric thiophenophenyl tropanes were in general found to be comparatively poor monoamine transporter binders, but significant gains of affinity of up to 45-fold could be achieved with selected dimeric chlorophenyl tropanes compared to the parent monomer. This observation implies that a secondary binding site that has affinity for phenyl tropanes, most likely the putative S2 site, is located within 13A of the primary central S1 binding site.
Nielsen
Susan
S
Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark.
Pedersen
Christian M
CM
Hansen
Signe Grann
SG
Petersen
Mikkel Due
MD
Sinning
Steffen
S
Wiborg
Ove
O
Jensen
Henrik Helligsø
HH
Bols
Mikael
M
D001667:Binding, Competitive; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D003959:Diamines; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes