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Figure 10. The structures of fluoxetine (a) and nisoxetine (b) and the fluoxetine analogs FD2 and FD4 (c)

Figure 10 The structures of fluoxetine (a) and nisoxetine (b) and the fluoxetine analogs FD2 and FD4 (c)

Related Figures (14)

The structure was generated in Discovery Studio 2015 V16.1.0.15350 from the Protein Data Bank (PDB) structure 5173 and further annotated in Microsoft Office, Power Point 2016 MSO (32 bit).
The structure was generated in Discovery Studio 2015 V16.1.0.15350 from the Protein Data Bank (PDB) structure 5173 and further annotated in Microsoft Office, Power Point 2016 MSO (32 bit).
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit).
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit).
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). Figure 3. Structures of sertraline, fluoxetine, and escitalopram
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). Figure 3. Structures of sertraline, fluoxetine, and escitalopram
Figure 4. Structure of sertraline’s lead compound, tametraline Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit).
Figure 4. Structure of sertraline’s lead compound, tametraline Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit).
CYP= Cytochrome P450 MAO= Monoamine oxidase Black circles indicate chiral centers in sertraline. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit
CYP= Cytochrome P450 MAO= Monoamine oxidase Black circles indicate chiral centers in sertraline. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit
a. The binding of sertraline and leucine to the bacterial LeuT. b. 2D representation of the common amino acid residues involved in the binding of both sertraline and leucine. Images were generated in Discovery Studio 2015 V16.1.0.15350 from the Protein Data Bank (PDB) structure 3GWU.
a. The binding of sertraline and leucine to the bacterial LeuT. b. 2D representation of the common amino acid residues involved in the binding of both sertraline and leucine. Images were generated in Discovery Studio 2015 V16.1.0.15350 from the Protein Data Bank (PDB) structure 3GWU.
CCA= 2-Oxo-2H-1-benzopyran-3-carboxylate SerH= sertraline in its protonated form Dashed lines indicate intermolecular hydrogen bonds. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit) from Escudero et al. (2016).
CCA= 2-Oxo-2H-1-benzopyran-3-carboxylate SerH= sertraline in its protonated form Dashed lines indicate intermolecular hydrogen bonds. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit) from Escudero et al. (2016).
SerH= sertraline in its protonated form. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit) from Escudero et al. (2017) (a) and Martini et al. (2017) (b).
SerH= sertraline in its protonated form. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit) from Escudero et al. (2017) (a) and Martini et al. (2017) (b).
Figure 9. The metabolism of fluoxetine CYr= Cytochrome F45U Red, blue and black colors refer to the major, moderate and minor metabolic pathways, respectively. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit)
Figure 9. The metabolism of fluoxetine CYr= Cytochrome F45U Red, blue and black colors refer to the major, moderate and minor metabolic pathways, respectively. Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit)
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit).
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit).
a,b. Escitalopram binding to the central binding site of the hSERT. 3D image (a) from the RSCB PDB (rcsb.org) of PDB 5173 (Coleman et al, 2016). 2D image (b) was generated in Discovery Studio V16.1.0.15350 from the Protein Data Bank (PDB) structure 5173. c. Allosteric binding slows down the dissociation from the primary binding site. Image was generated in Discovery Studio V16.1.0.15350 from the PDB structure 5173 and further annotated in Microsoft Office, Power Point 2016 MSO (32 bit). Citalopram (Figure 12) was first synthesized in 971 from the highly selective NE reuptake inhibi- tor talopram (Figure 12), a compound synthesized hrough a series of reactions and ring closure strategies from phthalide (Boges and Sanchez, 2012). The pharmacological activity of citalopram is primarily attributable to the S enantiomer, while the activity of the R enantiomer is reportedly 30-40 times weaker both in vitro and in vivo (Sanchez et al., 2004). The binding of escitalopram to the central binding site (S1) of the thermostable 3 mutation bearing hSERT (ts3 hSERT) has recently been reported by Coleman et al. (2016). In this model, the amine group of escitalopram
a,b. Escitalopram binding to the central binding site of the hSERT. 3D image (a) from the RSCB PDB (rcsb.org) of PDB 5173 (Coleman et al, 2016). 2D image (b) was generated in Discovery Studio V16.1.0.15350 from the Protein Data Bank (PDB) structure 5173. c. Allosteric binding slows down the dissociation from the primary binding site. Image was generated in Discovery Studio V16.1.0.15350 from the PDB structure 5173 and further annotated in Microsoft Office, Power Point 2016 MSO (32 bit). Citalopram (Figure 12) was first synthesized in 971 from the highly selective NE reuptake inhibi- tor talopram (Figure 12), a compound synthesized hrough a series of reactions and ring closure strategies from phthalide (Boges and Sanchez, 2012). The pharmacological activity of citalopram is primarily attributable to the S enantiomer, while the activity of the R enantiomer is reportedly 30-40 times weaker both in vitro and in vivo (Sanchez et al., 2004). The binding of escitalopram to the central binding site (S1) of the thermostable 3 mutation bearing hSERT (ts3 hSERT) has recently been reported by Coleman et al. (2016). In this model, the amine group of escitalopram
Figure 12. The structures of the lead talopram, and the two enantiomers of citalopram Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). Citalopram and its derivatives
Figure 12. The structures of the lead talopram, and the two enantiomers of citalopram Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). Citalopram and its derivatives
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). Figure 14. The structure of escitalopram and its analogs (a) and the most potent dimethyl citalopram (b)
Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). Figure 14. The structure of escitalopram and its analogs (a) and the most potent dimethyl citalopram (b)
Figure 15. Generalized binding interactions of sertraline, fluoxetine, and escitalopram Residues with strong and relatively strong contributions are shown in black and grey (a), respectively. Moieties significant for binding interactions are shown in blue and green (b). Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). effect profile compared to those of TCAs and MAOIs, SSRIs show some limitations, such as a delayed onset in the antidepressant effect (4-6 weeks), only about 65 % of patients respond to treatment, and occasionally exhibit sexual dysfunction side effects (Sharma H, Santra S, 2015; Marks et al., 2008). Hence, novel drug structures with improved pharmacokinetic and side effect profiles are in demand. Recently synthesized sertraline salts showed enhanced antidepressant activities and, in some cases, were also able to overcome anorexic symptoms apparent in depressed patients. New derivatives of escitalopram helped to map the allosteric binding site in the hSERT and also led to the design of new citalopram analogs, such as dimethyl citalopram, a potent allosteric inhibitor of hSERT. Binding studies of fluoxetine and hSERT provided useful information on the key determinants in the fluoxetine binding and led to the design of further fluoxetine and nisoxetine derivatives, such as FD2 and FD4 that proved to be efficient in DA reuptake inhibition in the treatment of cocaine addiction.
Figure 15. Generalized binding interactions of sertraline, fluoxetine, and escitalopram Residues with strong and relatively strong contributions are shown in black and grey (a), respectively. Moieties significant for binding interactions are shown in blue and green (b). Structures were generated in BioviaDraw, 2016, V16.1 9 (32 bit). effect profile compared to those of TCAs and MAOIs, SSRIs show some limitations, such as a delayed onset in the antidepressant effect (4-6 weeks), only about 65 % of patients respond to treatment, and occasionally exhibit sexual dysfunction side effects (Sharma H, Santra S, 2015; Marks et al., 2008). Hence, novel drug structures with improved pharmacokinetic and side effect profiles are in demand. Recently synthesized sertraline salts showed enhanced antidepressant activities and, in some cases, were also able to overcome anorexic symptoms apparent in depressed patients. New derivatives of escitalopram helped to map the allosteric binding site in the hSERT and also led to the design of new citalopram analogs, such as dimethyl citalopram, a potent allosteric inhibitor of hSERT. Binding studies of fluoxetine and hSERT provided useful information on the key determinants in the fluoxetine binding and led to the design of further fluoxetine and nisoxetine derivatives, such as FD2 and FD4 that proved to be efficient in DA reuptake inhibition in the treatment of cocaine addiction.
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