Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3beta-(4'-aminophenyl)-2beta-tropanemethanol.
A series of cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol sebacic acid ester/amide (5e) had a Ki of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.
Carroll
F Ivy
FI
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA. fic@rti.org
Blough
Bruce E
BE
Huang
Xiaodong
X
Nie
Zhe
Z
Mascarella
S Wayne
SW
Deschamps
Jeffrey
J
Navarro
Hernán A
HA
D000818:Animals; D001667:Binding, Competitive; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C513000:4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-hexadecahydro-23-methyl-14,17-etheno-19,22-imino-1H-cyclohept(c)(1,9)oxaazacyclononadecine-3,12-dione; C512999:5,6,7,8,10,14a,15,16,17,18,19,19a-dodecahydro-20-methyl-11,14-etheno-16,19-iminocyclohept(c)(1,9)oxaazacyclohexadecine-3,9(1H,4H)-dione; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; D003042:Cocaine