452062-33-8Relevant academic research and scientific papers
Structure-activity relationship comparison of (S)-2β-substituted 3α-(bis[4-fluorophenyl]methoxy)tropanes and (R)-2β-substituted 3β-(3,4-dichlorophenyl)tropanes at the dopamine transporter
Zou, Mu-Fa,Kopajtic, Theresa,Katz, Jonathan L.,Newman, Amy Hauck
, p. 2908 - 2916 (2007/10/03)
Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2β-carboalkoxy-3α-(bis[4-fiuorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2β-substituted 3β-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [3H]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (Ki = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato-(16) (S)-2β-carbophenylethoxy-3α-(bis[4-fluorophenyl] methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC50 = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.
Enantioselective synthesis of S-(+)-2β-carboalkoxy-3α-[bis(4-fluorophenyl)methoxy]tropanes as novel probes for the dopamine transporter
Zou, Mu-Fa,Agoston, Gregory E.,Belov, Yuri,Kopajtic, Theresa,Katz, Jonathan L.,Newman, Amy Hauck
, p. 1249 - 1252 (2007/10/03)
Synthesis of a series of pure S-(+)-2β-carboalkoxy-3α-[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 (Ki=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 3α-[bis(4-fluorophenyl)methoxy]tropane series is well tolerated at the DAT but not at SERT (Ki=690-2040 nM), or muscarinic M1 receptors (Ki=133-4380 nM) resulting in highly selective DAT ligands that may provide new leads toward a cocaine-abuse therapeutic.
