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Amy Hauck Newman - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)Tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [(3)H]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 (K(i) = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes demonstrated a significant decrease in DAT binding potency (IC(50) = 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.
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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
Journal of Medicinal Chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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enantioselective synthesis of s 2β carboalkoxy 3α bis 4 fluorophenyl methoxy Tropanes as novel probes for the dopamine transporter
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Gregory E Agoston, Yuri Belov, Amy Hauck NewmanAbstract:Abstract 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.
Alexander Shivanyuk - One of the best experts on this subject based on the ideXlab platform.
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selective synthesis of exo spiro 2 2 difluorocyclopropane 3 2 Tropanes
Synthesis, 2020Co-Authors: Andrii Gerasov, Aleksandr Yu. Mandzhulo, Volodymyr Fetyukhin, Oleg Lukin, Grygoriy A Dolgonos, Alexey Ryabitsky, Alexander ShivanyukAbstract:Conformationally restrained exo-isomers of N-Boc-protected spiro[2′,2′-difluorocyclopropane-3′,2′-Tropanes] were synthesized in 62–83% yield via absolutely diastereoselective cycloaddition of CF2, generated in situ from Me3SiCF3/NaI in refluxing THF, to double bonds of 3-alkylideneTropanes. Standard removal of Boc protecting groups afforded corresponding exo-spiro[2′,2′-difluorocyclopropane-3′,2′-tropane] hydrochlorides in 82–94% yields. DFT and CCSD(T) calculations revealed that the observed exo-selectivity of difluorocarbene addition is likely to be caused by a lower activation barrier of the exo-difluorocyclopropanation compared to the endo-reaction.
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Selective synthesis of N-protected exo-spiro[oxirane-3,2′-Tropanes]
Organic Chemistry Frontiers, 2019Co-Authors: Aleksandr Yu. Mandzhulo, Iryna Vashchenko, Andrii Gerasov, Mykhaylo V. Vovk, Eduard B. Rusanov, Volodymyr Fetyukhin, Oleg Lukin, Alexander ShivanyukAbstract:N-Cbz- and N-Boc-protected exo-spiro[oxirane-3,2′-Tropanes] were obtained in 62–75% yield via either epoxidation or hydroxybromination/dehydrobromination of the corresponding alkenes. Deprotection of the Cbz-exo-epoxide afforded the corresponding tropane containing an exo-oxirane fragment and a secondary amino group.
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selective synthesis of n protected exo spiro oxirane 3 2 Tropanes
Organic chemistry frontiers, 2019Co-Authors: Aleksandr Yu. Mandzhulo, Iryna Vashchenko, Andrii Gerasov, Mykhaylo V. Vovk, Eduard B. Rusanov, Volodymyr Fetyukhin, Oleg Lukin, Alexander ShivanyukAbstract:N-Cbz- and N-Boc-protected exo-spiro[oxirane-3,2′-Tropanes] were obtained in 62–75% yield via either epoxidation or hydroxybromination/dehydrobromination of the corresponding alkenes. Deprotection of the Cbz-exo-epoxide afforded the corresponding tropane containing an exo-oxirane fragment and a secondary amino group.
Mu-fa Zou - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)Tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [(3)H]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 (K(i) = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes demonstrated a significant decrease in DAT binding potency (IC(50) = 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.
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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
Journal of Medicinal Chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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enantioselective synthesis of s 2β carboalkoxy 3α bis 4 fluorophenyl methoxy Tropanes as novel probes for the dopamine transporter
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Gregory E Agoston, Yuri Belov, Amy Hauck NewmanAbstract:Abstract 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.
Jonathan L. Katz - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)Tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [(3)H]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 (K(i) = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes demonstrated a significant decrease in DAT binding potency (IC(50) = 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.
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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
Journal of Medicinal Chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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enantioselective synthesis of s 2β carboalkoxy 3α bis 4 fluorophenyl methoxy Tropanes as novel probes for the dopamine transporter
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Gregory E Agoston, Yuri Belov, Amy Hauck NewmanAbstract:Abstract 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.
Theresa Kopajtic - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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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
Journal of medicinal chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)Tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [(3)H]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 (K(i) = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis[4-fluorophenyl]methoxy)Tropanes demonstrated a significant decrease in DAT binding potency (IC(50) = 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.
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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
Journal of Medicinal Chemistry, 2003Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Amy Hauck NewmanAbstract: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-fluorophenyl]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 bindin...
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enantioselective synthesis of s 2β carboalkoxy 3α bis 4 fluorophenyl methoxy Tropanes as novel probes for the dopamine transporter
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Mu-fa Zou, Theresa Kopajtic, Jonathan L. Katz, Gregory E Agoston, Yuri Belov, Amy Hauck NewmanAbstract:Abstract 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.