Interaction of Serotonin and Fluoxetine: Toward Understanding the

J. Phys. Chem. B 2009, 113, 14529–14535

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Interaction of Serotonin and Fluoxetine: Toward Understanding the Importance of the Chirality of Fluoxetine (S form and R form) Prabhat K. Sahu,*,†,‡ Chun-Hung Wang,‡ and Shyi-Long Lee*,‡ Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland, 97074 Wu¨rzburg, Germany, and Department of Chemistry and Biochemistry, National Chung Cheng UniVersity, Chia -Yi, 621 Taiwan ReceiVed: July 27, 2009; ReVised Manuscript ReceiVed: August 28, 2009

The present investigation reports the importance of the S and R forms of fluoxetine, as an antidepressant with regards to the chirality taking different types of interactions associated with the neurotransmitter, serotonin. The goal of the present study is to provide predictions and to help experimental and theoretical studies toward understanding the chirality of fluoxetine in drug-ligand interaction, associated with serotonin-reuptake inhibitor drug design studies. Several different conformations for serotonin and fluoxetine complexes have been considered for quantum mechanical calculations. Both the S and R forms of fluoxetine associated with serotonin and fluoxetine complexes are found to be similar in total energy and binding energy values. The present study also supports the conformational effect of the 3-phenyl group of fluoxetine as stereo independent and is consistent with in vitro and in vivo data which indicates that the the eudismic ratio of fluoxetine enantiomers is near unity. The calculated highest stabilization energy values, binding energy values, both in the gas and aqueous phases at MP2/6-31+G*//B3LYP/6-31+G* identify the most possible stable conformer for the serotonin-fluoxetine complex. Introduction Chirality introduces marked selectivity, and often specificity, in drug action.1 The interaction of enantiomers with pharmacological receptors can be explained as a hand fits to a glove. Such receptors are often chiral, and the “right-” or “left-handed” drug will only fit to the molecular receptor at the desired site of action.2 Fluoxetine has been introduced as a potent antidepressant with a safer treatment alternative to the other two classes of drugs used to treat depressed patients: the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs), having an improved side effect profile.3,4 The pharmacological effect of fluoxetine takes place via inhibition of the presynaptic serotonin-reuptake carrier of neurons.5 For the last several years, the mechanism to understand the mode of action of these antidepressant drugs on their direct target, the serotonin transport protein, and possible regulatory mechanisms with respect to long-term alleviation of depression, although having been investigated both neurobiologically and clinically, are not yet fully understood. Fluoxetine is used therapeutically as the racemate, and most published pharmacology studies were conducted with the racemate. The two enantiomers have been obtained in optically pure form, and some of the pharmacological features of these two compounds have also been reported. Wong et al. showed that the (+) isomer was slightly more potent than the (-) isomer as a serotonin-reuptake inhibitor in rat cortical synaptosomes.6 Fuller and Snoddy demonstrated that the dextrorotatory isomer of fluoxetine was slightly more potent than the levorotatory isomer as an antagonist of p-chloroamphetamine-induced depletion of whole brain serotonin concentrations in rats.7 To date, there appears to be no evidence that either single enantiomer is preferable to racemic fluoxetine. * E-mail: [email protected] (P.K.S.) and [email protected] (S.-L.L.). † Universita¨t Wu¨rzburg. ‡ National Chung Cheng University.

In this report, the importance of the S and R forms of fluoxetine, as an antidepressant with regard to the chirality, has been considered to investigate different type of interactions, associated with the neurotransmitter, serotonin, using different quantum chemical methods. The goal of the present study is to provide predictions and to help experimental and theoretical studies toward understanding the chirality of fluoxetine in drug-ligand interactions, associated with serotonin-reuptake inhibitor drug design studies. To the best of our knowledge, no detailed studies have been found to date which enhance the understanding of the molecular interaction of fluoxetine with serotonin. Serotonin (5-hydroxytryptamine, 5-HT) acts as a neurotransmitter in the central nervous system (CNS) and it influences several physiological processes such as temperature regulation, appetite, sexual behavior, and sleep. Serotonin also plays important role in regulating smooth muscle function in the cardiovascular and gastrointestinal systems. Theoretical investigations for the gas phase and aqueous solution conformational analysis for protonated8 and neutral9 serotonin have been reported. More recently, LeGreve et al. have reported the resonant two-photon ionization (R2PI), laser-induced fluorescence (LIF), UV-UV hole-burning, resonant ion-dip infrared (RIDIR), and fluorescence-dip infrared (FDIR) spectra of isolated serotonin cooled in a supersonic expansion.10 Other than the molecular interaction of fluoxetine with serotonin, previous experimental investigations demonstrate that fluoxetine is a highaffinity ligand and a potent inhibitor of the serotonin transporter found in the human placental brush-border membrane11 and brain tissue.12 Computational Details The initial geometries of several different conformations for the interaction of serotonin and fluoxetine are identified in the HyperChem 7.5 package by molecular mechanics method using the AMBER13 force field. The resulting six different conformations for serotonin and fluoxetine complexes have been con-

10.1021/jp907151n CCC: $40.75  2009 American Chemical Society Published on Web 09/29/2009

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sidered for quantum mechanical calculations via an ab initio and density functional theory (DFT) method. All these different conformations have been optimized at the B3LYP/6-31+G* 14 level. Single point calculations at MP2/6-31+G*//B3LYP/631+G* 15 have also been carried out to better estimate the hydrogen bonding strengths. Harmonic vibrational frequency has also been analyzed for serotonin, fluoxetine monomers (with both racemic forms) at the B3LYP/cc-pVTZ16 level of theory. The vibrational analysis obtained for the serotonin monomer has been compared to previously reported van Mourik and Emson’s calculated results9 and with recently reported experimental results.10 The vibrational frequency analysis for all the six stable serotonin-fluoxetin complexes have also been carried out at B3LYP/6-31+G*. To analyze the solvent polarity effect, the COSMO approach17 has also been taken into account at the MP2/6-31+G*//B3LYP/6-31+G* level. All the electronic structure calculations are performed by using the Gaussian 03 package.18 Results and Discussion 1. Serotonin and Fluoxetine Monomers. The geometry parameters of serotonin monomer (5-hydroxytryptamine, 5-HT) and fluoxetine monomers with both racemic forms have been obtained at the B3LYP/6-31+G* and B3LYP/cc-pVTZ levels of theory. Figure 1.1 (cf the Supporting Information) shows the geometry optimized structure of serotonin monomer using the B3LYP/6-31+G* method. Figure 1.2 (cf the Supporting Information) shows the geometry optimized structure of the fluoxetine S form using the B3LYP/6-31+G* method. Compared with van Mourik and Emson’s computed result, Gpy(out) and Gph(out) are found as the two most stable minima, the lone pair in the ethylamine group is oriented away from the indole ring and one of the ethylamine hydrogens is directed toward the indole π-cloud. Our obtained results are similar to van Mourik and Emson’s computed result,9 but the orientation of the hydroxyl group is directed away from the ethylamine group, which is also supported by Alagona et al.8 and LeGreve et al.10 It has also been found that the relative energy difference between the anti and syn conformation is within the range 0.1-0.4 kcal/ mol.10 We also note that the results obtained at B3LYP/cc-pVTZ and B3LYP/6-31+G* are found to be very similar, and hence, we have chosen the B3LYP/6-31+G* method for our further calculations and discussions, as compared to the larger B3LYP/ cc-pVTZ to meet with the high computational cost. Figure 1.3 (cf the Supporting Information) shows the calculated IR spectra of serotonin and fluoxetine monomers with both racemic forms at the B3LYP/cc-pVTZ level of theory. There are other theoretical studies8 about the IR spectra of various conformers of serotonin monomer. Table 1.1 (cf the Supporting Information) lists the higher stretching frequencies scaled with a factor of 0.9603 as for the B3LYP method for the serotonin monomer. From Table 1.1, our results are in good agreement with the experimental Fourier transform infrared (FTIR) spectrum.9,10 In serotonin monomer, alkyl chain CH stretch bands are predicted to lie between 2840 and 2950 cm-1, the aromatic CH stretches between 3020 and 3110 cm-1, and the NH stretches associated with the amine group between 3340 and 3420 cm-1. The OH and indole NH stretch are close to each other, and the aromatic CH stretches are rather similar. The calculated harmonic vibrational frequencies and intensities of the fluoxetine monomers with both racemic forms at the B3LYP/cc-pVTZ level of theory are listed in Table 1.2 (cf the Supporting Information). From Table 1.2, in both forms of fluoxetine, alkyl chain CH stretch bands lie between 2810 and

Figure 1. Conformer 1 of the serotonin-fluoxetine complex using the B3LYP/6-31+G* method. (a) S form of fluoxetine. (b) R form of fluoxetine. Atom color: carbon (grey), hydrogen (white), oxygen (red), nitrogen (blue), and fluorine (cyan).

2980, the aromatic CH stretches between 3020 and 3110 cm-1, and the NH stretches associated with the ethylamine group near 3380 ( 15 cm-1. Because of the lack of experimental evidence, we note the vibrational frequencies as a point of reference for the future experimental work. 2. Serotonin-Fluoxetine Complex. 2.1. Geometry Parameters.Sixdifferentstableconformationsfortheserotonin-fluoxetine complex have been investigated. According to the molecular dynamics (MD) simulation of serotonin and 5-HT2A receptor, the NH2 group of serotonin can form two strong hydrogen bonds withD155andS159of5-HT2A receptor,N-H(serotonin)· · ·O(aspartate) and O-H(serine) · · · N(serotonin),19,20 and it also reveals that the ethylamine group of serotonin does not form hydrogen bonds with fluoxetine. Figures 1-6 show the six different stable

Interaction of Serotonin and Fluoxetine


conformations for the serotonin-fluoxetine complex at the B3LYP/6-31+G* level of theory. Table 1.3 (cf the Supporting Information) shows the geometrical parameters of serotonin monomer and serotonin in the serotonin-fluoxetine complex using the B3LYP/6-31+G* method. Because of the chirality of fluoxetine, the stable structures of serotonin in each form of fluoxetine differ. The differences of the dihedral angles γC, γN, C47-C44-N42-H41, and C47-C44-N42-H43 in the six conformers are very similar, as compared to either the S or R forms of fluoxetine. Table 1.4 (cf the Supporting Information) shows the geometrical parameters of fluoxetine monomer and fluoxetine in the serotonin-fluoxetine complex using the B3LYP/6-31+G* method. Because of the chirality of fluoxetine, the dihedral

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angles C32-C29-C16-O15, C32-C29-C16-O15, C32-C29-C16C18, and C29-C16-O15-C3 have nearly opposite signs in the S and R forms for all six conformers. 2.2. Hydrogen Bonding Parameters. Table 1 lists the hydrogen bonding parameters for all six different conformations of the serotonin-fluoxetine complex at the B3LYP/6-31+G* level. It has been observed that the interaction of serotonin and fluoxetine are mainly due to hydrogen bonding, which follows two different approaches. One is through the hydroxyl group of serotonin (N · · · H-O or F · · · H-O) and the other through the indole NH (F · · · H-N or N · · · H-N). Both of these two kinds of hydrogen bond interactions are observed for conformers 1-4, whereas only N · · · H-N type interactions were observed for conformers 5 and 6. In conformers 1 and 2, the hydrogen

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bond involved through the hydroxyl group of serotonin, N35 · · · H65 (N · · · H-O type) are less than 2.0 Å, and the bond angle ∠N35H65O64 are more linear as compared to those hydrogen bond involved through the indole NH, F14 · · · H56 (F · · · H-N type). In conformer 3 and 4, it has been observed that the hydrogen bonds involved through the indole NH, N35 · · · H56 (N · · · H-N type), are around 2.0 Å and the bond angles ∠N35H56N55 are more linear as compared to those hydrogen bonds involved through the hydroxyl group of serotonin, F14 · · · H65 (F · · · H-O type). In conformers 5 and 6, hydrogen bonds only involved through the indole NH, N35 · · · H56 (N · · · H-N type), are observed, the bond length N35 · · · H56 is around 2.0 Å, and the bond angles ∠N35H56N55 are all nearly linear. Rotational constants for the six stable conformers of serotonin-fluoxetine complexes using B3LYP/6-31+G* are


listed in Table 1.5 (cf the Supporting Information) for future reference and experimental support. 2.3. Energetics. Table 1.6 (cf the Supporting Information) shows the total energy for the six stable conformers of serotonin-fluoxetine complexes calculated both at the gas and aqueous phases with the B3LYP/6-31+G* and MP2/6-31+G*// B3LYP/6-31+G* methods, using the COSMO approach. It is interesting to note that for all these six different stable conformers, the stabilization energies are found to be similar (within 3 kcal/mol) both in the gas phase and even in the aqueous phase. However, the MP2 method is of course, well-

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J. Phys. Chem. B, Vol. 113, No. 43, 2009 14533 TABLE 1: Hydrogen Bonding Parameters for the Six Stable Conformers of Serotonin-Fluoxetine Complexesa conformers 1 S form R form 2 S form R form 3 S form R form 4 S form R form 5 S form R form 6 S form R form

N35 · · · H65s O64

F14 · · · H56s N55

N35 · · · H56s N55

F14 · · · H65s O64

1.90/155.7 1.90/155.7

3.05/137.2 3.05/137.1

-/-/-

-/-/-

1.89/166.8 1.89/167.7

2.98/140.9 3.01/140.8

-/-/-

-/-/-

-/-/-

-/-/-

2.15/154.1 2.15/154.2

2.46/150.7 2.45/150.8

-/-/-

-/-/-

2.11/166.0 2.10/167.2

2.40/153.3 2.44/152.4

-/-/-

-/-/-

2.02/178.2 2.02/178.1

-/-/-

-/-/-

-/-/-

2.02/176.4 2.02/176.7

-/-/-

a All the H-bond distances are in angstroms; the corresponding bond angles are in degrees.

TABLE 2: Binding Energies for the Six Stable Conformers of Serotonin-Fluoxetine Complexesa conformers 1 S form R form 2 S form R form 3 S form R form 4 S form R form 5 S form R form 6 S form R form

MP2/6-31+G*// MP2/6-31+G*// B3LYP/ 6-31+G* b B3LYP/6-31+G* b,d B3LYP/6-31+G* c,d -7.78 -7.78

-21.94 (3.80) -21.93 (3.80)

-11.50 (4.15) -11.50 (4.15)

-7.49 -7.53

-20.65 (5.19) -20.88 (5.21)

-11.70 (6.14) -11.82 (6.20)

-5.28 -5.28

-19.94 (7.36) -19.95 (7.36)

-8.21 (8.77) -8.20 (8.78)

-4.97 -4.98

-17.98 (8.24) -17.91 (8.25)

-7.55 (9.88) -7.54 (9.90)

-6.26 -6.27

-11.81 (8.09) -11.74 (8.09)

-7.02 (9.62) -6.99 (9.62)

-6.28 -6.28

-11.66 (7.85) -11.58 (7.86)

-7.19 (9.15) -7.14 (9.17)

a All the energy values are in kilocalories per mole. b Gas phase. Aqueous phase. d The corresponding dipole moment values (in Debye) are given in parentheses.

c


known to account for the correlation effect and to better estimate the energy values as compared to B3LYP method, as reflected in the listed values. Table 2 shows the gas phase binding energy for the six stable conformers of serotonin-fluoxetine complexes using B3LYP/ 6-31+G* and MP2/6-31+G*//B3LYP/6-31+G* methods. The calculated binding energy values for both the S and R forms of each conformer are found to be very similar, which supports the finding that eudismic ratio21 of fluoxetine enantiomers is near unity. However, in the B3LYP/6-31+G* method, the order of the stability of binding energies of the six conformers is 1 > 2 > 5-6 > 3 > 4. From this stability ordering, it is clear that the nature of hydrogen bond interactions for each conformer described in the earlier section is playing an important role,

whereas the conformational effect of the 3-phenyl group of fluoxetine is stereo independent. For conformers 1 and 2, the two hydrogen bonds involved through the hydroxyl group of serotonin, N35 · · · H65 (N · · · H-O type), and the other hydrogen bond involved through the indole NH, F14 · · · H56 (F · · · H-N type), are found to be associated with higher interaction as compared to those of conformers 3 and 4, the hydrogen bond involved through the indole NH, N35 · · · H56 (N · · · H-N type), and the other hydrogen bond involved through hydroxyl group of serotonin, F14 · · · H65 (F · · · H-O type). Though in conformers 5 and 6, hydrogen bonds are only involved through the indole NH, N35 · · · H56 (N · · · H-N type), the more linear hydrogen bond angles ∠N35H56N55 for conformers 5 and 6 provide evidence in support of their higher stability ordering, as compared to conformers 3 and 4. To better estimate the binding energy values with correlation effect and dispersion contribution taken into account, in the MP2/6-31+G*//B3LYP/6-31+G* method, the

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TABLE 3: Computed Reaction Enthalpy for the Six Stable Conformers of Serotonin-Fluoxetine Complexes using B3LYP/6-31+G* at 298.15 Ke conformers 1 S Form R Form 2 S Form R Form 3 S Form R Form 4 S Form R Form 5 S Form R Form 6 S Form R Form

∆EBOa

∆Etransb

∆Erotb

∆Evibb

∆ZPEc

∆Hrxnd

-7.78 -7.78

-0.89 -0.89

-0.89 -0.89

2.45 2.45

1.56 1.56

-5.55 -5.55

-7.49 -7.53

-0.89 -0.89

-0.89 -0.89

2.27 2.29

1.29 1.33

-5.71 -5.69

-5.28 -5.28

-0.89 -0.89

-0.89 -0.89

2.35 2.35

1.35 1.35

-3.36 -3.36

-4.97 -4.98

-0.89 -0.89

-0.89 -0.89

2.24 2.22

1.21 1.20

-3.30 -3.34

-6.26 -6.27

-0.89 -0.89

-0.89 -0.89

2.23 2.23

1.05 1.05

-4.76 -4.77

-6.28 -6.28

-0.89 -0.89

-0.89 -0.89

2.27 2.26

1.12 1.10

-4.67 -4.70

The difference in binding energy values for conformers 2 and 1 is within 0.3 kcal/mol. In the aqueous phase, due to the electronic polarization effect (which is reflected in the enlargement of the dipole moment of the corresponding conformers upon condensation (see Table 2)), we also observed around 10 kcal/mol difference in its binding energy values as compared to those obtained in the gas phase for all six stable conformers of serotonin-fluoxetine complexes. Conclusion

a ∆EBO ) electronic binding energy. b ∆Etrans, ∆Erot, and ∆Evib are change in translational, rotational, and vibrational energy, respectively c ∆ZPE ) change in zero point vibrational energy, d ∆Hrxn ) reaction enthalpies e All the values are in kilocalories per mole.

trend for the calculated binding energy for all six different conformers is found to be 1 > 2 > 3 > 4 > 5 > 6 in contrast to those obtained with B3LYP/6-31+G*. The trend reversal for the binding energy values of conformers 3 and 4 is observed due to the contribution of the electron correlation and dispersion effect. However, the highest binding energy values are obtained for conformer 1 (21.94 kcal/mol for the S form and 21.93 kcal/ mol for the R form). Table 3 depicts the computed reaction enthalpy values for the six stable conformers of serotonin-fluoxetine complexes using B3LYP/6-31+G* at 298.15 K. The computed reaction enthalpy is given by the following equation

∆Hrxn ) ∆EBO + ∆Etrans + ∆Erot + ∆Evib + ∆ZPE Where, ∆EBO ) electronic bonding energy, ∆Etrans, ∆Erot, and ∆Evib are change in translational, rotational, and vibrational energy, and ∆ZPE ) zero point vibrational energy. From Table 3, it can be observed that the reaction enthalpy value for the S and R forms of each of the stable conformers are found to be same, which also indicates the that eudismic ratio21 of fluoxetine enantiomers is near unity. The calculated reaction enthalpy for conformer 2 is 5.71 kcal/mol for the S form and 5.69 kcal/mol for the R form as compared to conformer 1 (5.55 kcal/mol for both the S and R forms). The calculated reaction enthalpy values are in the order, 2 > 1 > 5-6 > 3-4. To analyze the solvent polarity effect on the binding energy of the six stable conformers of serotonin-fluoxetine complexes, we have also computed with MP2/6-31+G*//B3LYP/6-31+G* using COSMO approach. Table 2 lists these computed values and it is interesting to note that the binding energy values are in the order 2 > 1 > 3 > 4 > 5 > 6 in contrast to those obtained as 1 > 2 > 3 > 4 > 5 > 6 with the gas phase calculation at MP2/6-31+G*//B3LYP/6-31+G* in a qualitative sense. The highest binding energy values for conformer 2 are 11.7 kcal/ mol for the S form and 11.82 kcal/mol for the R form, and that for conformer 1 is 11.5 kcal/mol for both the S and R forms.

The geometric structures, harmonic vibrational frequencies for serotonin monomer and fluoxetine monomer (including both S and R forms) have been investigated, and possible comparison has been made with the earlier reported work.8-10 The initial geometries for the six different conformations of serotonin and fluoxetine complexes have been identified by a molecular mechanics method using the AMBER13 force field and considered for quantum mechanical calculations via an ab initio and density functional theory (DFT) method. The hydrogen bond interactions for the serotonin-fluoxetine complexes follow two different approaches. One is through hydroxyl group of serotonin (N · · · H-O or F · · · H-O) and the other through the indole NH (F · · · H-N or N · · · H-N). In the B3LYP/6-31+G* method, the binding energies of the six stable conformers are 1 > 2 > 5-6 > 3 > 4, which reveals that the nature of hydrogen bond interactions for each conformer is playing an important role and the conformational effect of the 3-phenyl group of fluoxetine is stereo independent. When the electron correlation effect and dispersion effect have been taken in to account by using the MP2/6-31+G*//B3LYP/6-31+G* method, the binding energy values are 1 > 2 > 3 > 4 > 5 > 6, in contrast to those obtained with B3LYP/6-31+G*. The calculated reaction enthalpy for conformer 2 is 5.71 kcal/mol for the S form and 5.69 kcal/mol for the R form as compared to conformer 1 (5.55 kcal/mol for both the S and R forms). In aqueous solvation, the binding energy values at MP2/6-31+G*//B3LYP/6-31+G* are 2 > 1 > 3 > 4 > 5 > 6 in contrast to those obtained as 1 > 2 > 3 > 4 > 5 > 6 with gas phase calculation in the qualitative sense. The difference in binding energy values for conformers 2 and 1 is within 0.3 kcal/mol. The present investigation confirms that conformer 2 as the most possible stable conformer in the aqueous phase out of the six different serotonin-fluoxetine complexes. These findings may provide assistance in future theoretical and experimental research for the interaction of serotonin and fluoxetine as potent drug-ligand interaction toward understanding the importance of the chirality of fluoxetine (S form and R form) for drug development of both enantiomers for different indication such as depression and migraines. We are interested in providing some computational insight to the earlier hypothesized5 three-dimensional orientation between the propanamine and (trifluoromethyl) phenoxy moeties of fluoxetine and various conformations of serotonin with regards to different types of hydrogen bond interactions, and we thus focus on the underlying conformational studies of fluoxetine, serotonin, and serotonin-fluoxetine complexes which should be of prime importance in this context at least in qualitative sense with regards to the role of hydrogen bond interaction. The present study supports the conformational effect of the 3-phenyl group as stereo independent and is consistent with in vitro and in vivo data which indicate that the eudismic ratio21 of fluoxetine enantiomers is near unity. The substituent effect of such biomolecular interaction is currently under investigation. We are also investigating the cation-π interaction for the protonated serotonin and the racemic fluoxetine.

Interaction of Serotonin and Fluoxetine Acknowledgment. This research is supported by the National Science Council (NSC) of Taiwan and the computational resource is partially supported by National Center for HighPerformance Computing (NCHC), Hsin-Chu, Taiwan. Supporting Information Available: Figures 1.1-1.3 and Tables 1.1-1.6. This material is available free of charge via Internet at http://pubs.acs.org. References and Notes (1) Tucker, G. T. Lancet 2000, 355, 1085–1087. (2) Ther. Lett. 2002; 45. (3) Neal, M. J. Medical Pharmacology at a Glance; Blackwell Publishing: New York, 2005. (4) Medicinal Chemistry and Drug DiscoVery; Burger, A., Ed.; John Wiley & Sons, Inc.: New York, 2006. (5) (a) Wong, D. T.; Horng, J. S.; Bymaster, F. P.; Hauser, K. L.; Molloy, B. B. Life Sci. 1974, 15, 471. (b) Wong, D. T.; Bymaster, F. P.; Horng, J. S.; Molloy, B. B. J. Pharmacol. Exp. Ther. 1975, 193, 804. (c) Robertson, D. W.; Jones, N. D.; Swartzendruber, J. K.; Yang, K. S.; Wong, D. T. J. Med. Chem. 1988, 31, 185–189. (6) Wong, D. T.; Bymaster, F. P.; Reid, L. R.; Fuller, R. W.; Perry, K. W. Drug DeV. Res. 1985, 6, 397. (7) Fuller, R. W.; Snoddy, H. D. Pharmacol., Biochem. BehaV. 1986, 24, 281. (8) (a) Alagona, G.; Ghio, C.; Nagy, P. I. J. Chem. Theory Comput. 2005, 1, 801–806. (b) Pratuangdejkul, J.; Jaudon, P.; Ducrocq, C.; Nosoongnoen, W.; Guerin, G.; Conti, M.; Loric, S.; Launay, J.; Manivet, P. J. Chem. Theory Comput. 2006, 2, 746–760. (c) Pisterzi, L. F.; Almeida, D. R. P.; Chass, G. A.; Torday, L. L.; Papp, J. G.; Varro, A.; Csizmadia, I. G. Chem. Phys. Lett. 2002, 365, 542–551. (d) Alagona, G.; Ghio, C. J. Mol. Structure: THEOCHEM 2006, 769, 123–134. (9) van Mourik, T.; Emson, L. E. V. Phys. Chem. Chem. Phys. 2002, 4, 5863–5871. Bayari, S.; Saglam, S.; Ustundag, H. F. J. Mol. Strcuture: THEOCHEM 2005, 726, 225–232 (the FTIR spectrum recorded with the KBr technique was obtained from Patir’s result). (10) LeGreve, T. A.; Baquero, E. E.; Zwier, T. S. J. Am. Chem. Soc. 2007, 129, 4028–4038.

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Interaction of Serotonin and Fluoxetine: Toward Understanding the

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