Synthesis of 2 beta-acyl-3 beta-aryl-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites in rat striatum and frontal cortex.
A novel entry to tropane analogs of cocaine was developed on the basis of the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine and serotonin (5-HT) 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 (as in WIN-35,428), and methyl or ethyl ketone moieties were present at the 2-position instead of the typical ester group. The series of analogs containing a 2-naphthyl group at the 3-position were most potent, with Ki values < 1 nM in binding to both dopamine and 5-HT transporters. Although the unsubstituted 2-naphthyl analog was nonselective at dopamine and 5-HT transport sites, other compounds were selective for either site. In general, compounds with relatively small substituents on the aromatic moiety (such as p-methyl or p-fluoro) were relatively selective for the dopamine transporters, while a p-isopropylphenyl derivative was selective for the 5-HT transport sites. This latter compound represents the first N-methyltropane derivative specific for 5-HT transporters. Resolution of two of the most significant analogs was achieved by HPLC on a chiral stationary phase; the active enantiomer of a 2-naphthyl analog exhibited Ki values of < 0.1 nM at both dopamine and 5-HT transporter sites.
Davies
H M
HM
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109.
Saikali
E
E
Huby
N J
NJ
Gilliatt
V J
VJ
Matasi
J J
JJ
Sexton
T
T
Childers
S R
SR
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005625:Frontal Lobe / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D011758:Pyrroles / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012238:Rhodium; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014316:Tritium
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011758:Pyrroles; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D014316:Tritium; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D012238:Rhodium; D003042:Cocaine