156774-35-5Relevant academic research and scientific papers
The Discovery of an Unusually Selective and Novel Cocaine Analog: Difluoropine. Synthesis and Inhibition of Binding at Cocaine Recognition Sites
Meltzer, Peter C.,Liang, Anna. Y.,Madras, Bertha. K.
, p. 2001 - 2010 (1994)
Cocaine is a stimulant drug with a high abuse liability. Although it inhibits several monamine transporters in the mammalian brain, its primary mechanism of action has been ascribed to its inhibition of the dopamine transporter. The synthesis, characterization, and receptor binding properties of all eight isomers of a unique tropane analog, 2-carbomethoxy-3-tropane is described. In addition, we report that the S-enantiomer, (S)-(+)-2β-carbomethoxy-3α-tropane, Difluoropine, is a potent (IC50 10.9 nM) and selective (324 ) ligand for the dopamine transporter.
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.
2-carbomethoxy-3-(diarylmethoxy)-1αH,5αH-tropane analogs: Synthesis and inhibition of binding at the dopamine transporter and comparison with piperazines of the GBR series
Meltzer, Peter C.,Liang, Anna Y.,Madras, Bertha K.
, p. 371 - 379 (2007/10/03)
We recently reported a new class of tropanes, based on benztropine, that bind uniquely, in the S-configuration, to the dopamine transporter. We have now extended this series to evaluate the effects of substituents on the nitrogen and the diarylmethoxy group. Herein we have described the synthesis and biological evaluation of a series of 2-carbomethoxy-3-(diaryl-methoxy)- 1αH,5αH-tropane (2-carbomethoxybenztropine) analogs. Examination of the binding data obtained for these compounds shows that while the 4,4'-difluoro compound is potent and selective for the dopamine transporter, introduction of larger groups such as 4,4'-dichloro, 4,4'-dibromo, 4,4'-diiodo, or 4,4'- dimethyl on the 3-diphenylmethoxy moiety reduces this potency. However, although introduction of only one group (e.g., 4-chloro, 4-bromo, 4-iodo, or 4-methyl) leads to a similar reduction of binding affinity, these monosubstituted 2-carbomethoxybenztropines are significantly more potent than the related disubstituted compounds. Finally, from the data for the N- substituted 2-carbomethoxybenztropine analogs, it is evident that steric bulk can be tolerated at the nitrogen site. A comparison of structure-activity relationship data for the tropanes, GBR analogs, and these benztropines indicates that the 2-carbomethoxy-benztropine analogs may be more like the GBR analogs in their mode of binding to the dopamine transporter than like the tropanes. This conclusion supports the notion that the binding site for (-)-cocaine [and the (1R)-tropanes] may differ from that of the 2- carbomethoxybenztropine analogs.
