Enantioselective synthesis of S-(+)-2beta-carboalkoxy-3alpha-[bis(4-fluorophenyl)methoxy]tropanes as novel probes for the dopamine transporter.
Synthesis of a series of pure S-(+)-2beta-carboalkoxy-3alpha-[bis(4-fluorophenyl)methoxy]tropanes (>99% ee) was achieved by employing a chiral amine-induced asymmetric reaction of tropinone with methyl cyanoformate as the key step. In this series, all of the S-(+)-enantiomers were 2-fold more potent than their racemic mixtures and all displayed high-affinity binding for DAT (K(i)=13-40 nM). These data support previous findings of significant divergence in structural requirements for high-affinity DAT binding among tropane-based inhibitors. Furthermore, the 2-substituent in the 3alpha-[bis(4-fluorophenyl)methoxy]tropane series is well tolerated at the DAT but not at SERT (K(i)=690-2040 nM), or muscarinic M(1) receptors (K(i)=133-4380 nM) resulting in highly selective DAT ligands that may provide new leads toward a cocaine-abuse therapeutic.
Zou
Mu-Fa
MF
Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Agoston
Gregory E
GE
Belov
Yuri
Y
Kopajtic
Theresa
T
Katz
Jonathan L
JL
Newman
Amy Hauck
AH
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D013237:Stereoisomerism; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D014326:Tropanes