Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site.
A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.
Davies
H M
HM
Department of Chemistry, State University of New York at Buffalo 14260-3000, USA.
Kuhn
L A
LA
Thornley
C
C
Matasi
J J
JJ
Sexton
T
T
Childers
S R
SR
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D027981:Symporters; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D002352:Carrier Proteins; D003042:Cocaine; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D014326:Tropanes; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; C011386:nisoxetine; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane