Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters.
Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). Inhibition of the DAT causes an increase of dopamine in the synapse with a resultant activation of postsynaptic receptors. The rapid onset and short duration of action of cocaine contribute to its high addictive potential. Consequently, the design of tropane analogues of cocaine that display longer onset times on the DAT and extended duration of action is driven by the need to develop cocaine medication. This study extends the exploration of bridge hydroxylated azabicyclo[3.2.1]octanes (tropanes). A series of 6- and 7-hydroxylated tropanes was prepared and evaluated biologically. Structure activity relationships lead to the following conclusions. Bridge hydroxylated tropanes retain biological enantioselectivity but display higher DAT versus SERT selectivity, particularly for the 3 alpha-aryl compounds as compared with the 3beta-aryl compounds, than the bridge unsubstituted analogues. The 7-hydroxyl compounds are more potent at the DAT than their 6-hydroxyl counterparts. The general SAR of the tropanes is maintained and the rank order of potencies based on substitution at the C3 position remains 3,4-dichloro > 2-naphthyl > 4-fluoro > phenyl.
Meltzer
P C
PC
Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, USA. Meltzer@organixinc.com
Wang
B
B
Chen
Z
Z
Blundell
P
P
Jayaraman
M
M
Gonzalez
M D
MD
George
C
C
Madras
B K
BK
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D003042:Cocaine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011699:Putamen / Q000378:metabolism; D011869:Radioligand Assay; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; D012701:Serotonin; D003042:Cocaine; D004298:Dopamine