Enhancing a CH-π interaction to increase the affinity for 5-HT 1A receptors

Article abstract of DOI:10.1021/ml4004843

An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT_1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared t

Full text of DOI:10.1021/ml4004843

Letter
pubs.acs.org/acsmedchemlett
Enhancing a CH−π Interaction to Increase the Affinity for 5‑HT1A
Receptors
Jean-Franco
Jacqueline Scuvee-Moreau,‡ and Sebastien Dilly†,‡
̧
is Liegeois,*,† Marc Lespagnard,† Elsa Meneses Salas,† Floriane Mangin,†
́
́
́
†Laboratory of Medicinal Chemistry and C.I.R.M., University of Lieg
‡Laboratory of Pharmacology and GIGA-Neuroscience, University of Lieg
̀
e, avenue de l′Ho
̂
pital, 1 (B36), B-4000 Lieg
̀
e 1, Belgium
e 1, Belgium
̀
e, avenue de l′Ho
̂
pital, 1 (B36), B-4000 Lieg
̀
S
* Supporting Information
ABSTRACT: An electrostatic interaction related to a
favorable position of the distal phenyl ring and a phenylalanine
residue in the binding pocket would explain the higher 5-HT1A
affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP)
analogue compared to the corresponding 4-phenylpiperazine
analogue. To explore a possible reinforcement of this
interaction to increase the affinity for 5-HT1A receptors,
different 4-substituted-phenyl analogues were synthesized and
tested. The most important increase of affinity is obtained with two electron-donating methyl groups in positions 3 and 5.
KEYWORDS: CH−π interaction, quinoxaline, carboxamide, arylpiperazine, electron-donating, docking
a
ecently, we reported that a 4-phenyl-1,2,3,6-tetrahydro-
pyridine (THP) analogue was shown to be favorable
Scheme 1
R
compared to the corresponding 4-phenyl-piperazine one in
terms of affinity for 5-HT1A receptors in a series of 4-
arylpiperazine-ethyl carboxamides.1 An electrostatic interaction
between the distal benzene ring of the molecule and a
phenylalanine residue (Phe 6.52) particularly in the 5-HT1A
receptor binding pocket was suggested by molecular modeling
approaches.2 The almost coplanar orientation of both rings
displayed in the 4-phenyl-THP compound appeared as an
important spatial requirement for an optimal interaction with
the 5-HT1A receptor in the present series. This orientation
should stabilize the ligand binding by an edge-to-face CH−π
interaction between the phenyl ring of the 4-phenyl-THP
compounds and the phenyl ring of the Phe 6.52 residue.2 This
would explain why the chemical modification of the piperazine
ring into THP is favorable for receptor affinity.
a
Reagents and conditions: (i) N-(un)substituted-4-phenylpiperazine
(or (un)substituted-4-phenyl-THP), K2CO3, ACN, reflux; (ii)
NH2NH2, EtOH, reflux; (iii) acyl chloride, Et3N, EtOAc, rt. R1: H,
4-F, 4-Cl, 4-Me, 3,5-diF, 3,5-diMe. R2: 2-naphthyl (3a−l), 2-
quinoxalinyl (4a−l). X−Y: N−CH2 or CCH.
The electron donating/withdrawing properties of an
aromatic substituent is an important factor for the electron
density of the aromatic ring and consequently for the capacity
of these rings to be involved in aromatic stacking interactions.3
Some studies have already shown the impact of the electronic
properties of the substituents on the stability of these
interactions in ligand−receptor binding.4,5 Therefore, by
increasing the electronic density with an electron-donating
group, we expected to reinforce the interaction between the
distal benzene ring and the Phe 6.52 residue. The substituents
were positioned either in position 4 or positions 3 and 5 of the
distal ring in order to avoid a sterical constraint if present in
position 2 or 6. To explore a possible opposite effect linked to
the electronic properties of the substituents, electron-with-
drawing atoms were also introduced. The THP derivatives were
tested, in parallel with the corresponding arylpiperazine
derivatives, for their affinity for 5-HT1A receptors. The intrinsic
activity of six selected compounds was also investigated using
an electrophysiological approach.
The target compounds were prepared by reaction of the
appropriate primary amine with the appropriate acyl chloride
(2-naphthoyl chloride or 2-quinoxaline chloride) as reported in
Scheme 1. The crude amines were synthesized following a
Gabriel procedure using the appropriate N-substituted
phthalimide analogues, which were obtained by reaction of an
adequate substituted N-phenylpiperazine (or substituted 4-
Received: November 26, 2013
Accepted: January 29, 2014
Published: January 29, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
phenyl-THP) with N-(2-bromoethyl)phthalimide in the
presence of potassium carbonate.
Table 2. Affinity for 5-HT1A Receptors and Physicochemical
Characteristics of Quinoxaline Carboxamide Derivatives
(4a−l)
Most N-arylpiperazine derivatives were obtained from
commercial sources and used without further purification.
Phthalimide derivatives are characterized and tested in parallel
in the in vitro binding model. Most substituted 4-aryl-THP
derivatives have been prepared by a Grignard reaction between
the adequate substituted-phenyl magnesium bromide and
commercially available N-Boc-4-piperidone according to similar
protocols as those reported in the literature.6−8 For 3,5-difluoro
and 3,5-dimethyl analogues, Grignard reagents were prepared
in the laboratory, while 4-methyl and 4-fluoro analogues were
purchased. After reaction, the N-Boc-piperidinol analogue is
dehydrated and deprotected by treatment with trifluoroacetic
acid in methylene chloride to give the appropriate THP
derivatives. With the 3,5-difluoro derivative, unexpectedly, the
hydroxyl group was not eliminated, and the piperidinol was
obtained with this procedure. Another approach using a
mixture of HBr and acetic acid led to the appropriate analogue.
Target compounds (3a−l and 4a−l) were isolated as the base
and further characterized before biological evaluation.
In vitro binding experiments were conducted on human
cloned 5-HT1A receptors expressed in CHO cells and used as
membrane preparations. The radioligand used was [3H]-8-OH-
DPAT. Experimental procedures for filtration and radioactivity
counting are the same used in our previous studies.1,9,10 Details
can be found in the Supporting Information. Values of affinity
for naphthyl (3a−l) and quinoxaline (4a−l) derivatives are
reported in Tables 1 and 2, respectively.
a
compd
amine
R1
Ki
pKa
log P
4a
4b
4c
4d
4e
4f
piperazine
THP
H
30.0 5.8
3.76 0.24
63.3 15.1
14.0 2.1
27.0 3.6
9.30 0.89
27.3 4.5
7.55 1.84
11.1 0.7
2.62 0.53
3.67 0.38
1.10 0.16
6.98
7.84
6.92
7.79
6.89
7.75
7.18
8.15
6.83
7.67
7.33
8.20
3.66
4.18
3.89
4.19
4.46
4.76
4.08
4.55
4.09
4.34
4.57
5.05
H
piperazine
THP
4-F
4-F
piperazine
THP
4-Cl
4-Cl
4g
4h
4i
piperazine
THP
4-Me
4-Me
piperazine
THP
3,5-diF
3,5-diF
3,5-diMe
3,5-diMe
4j
4k
4l
piperazine
THP
a
Ki in nM; mean SEM n ≥ 3.
density of the benzene ring might also reduce the interaction
with the residue in the binding pocket by more than a
deleterious sterical effect contrary to the chlorine or methyl
substituent in other derivatives. For the 3,5-difluoro analogues
(3i, 3j) and the 3,5-dimethyl analogues (3k, 3l), the affinity is
quite similar to that of the corresponding unsubstituted
derivatives (3a, 3b).
Table 1. Affinity for 5-HT1A Receptors and Physicochemical
Characteristics of Naphthalene Carboxamide Derivatives
(3a−l)
In the quinoxaline series, it appears that the unsubstituted
analogues (4a, 4b) possess a similar affinity as that of the
naphthyl congeners (3a, 3b). Substituted THP analogues (4b,
4d, 4f, 4h, 4j, 4l) have a higher affinity than the corresponding
piperazine derivatives (4a, 4c, 4e, 4g, 4i, 4k). The presence of a
fluorine in position 4 (4c, 4d) reduces the affinity in both THP
and piperazine series, and this might be related to the electron-
withdrawing properties of the fluorine. The presence of a
methyl group (4g, 4h) and a chlorine (4e, 4f) in the same
position leads to a smaller decrease of affinity in THP series in
comparison with the unsubstituted analogues (4a, 4b). The
presence of two substituents in positions 3 and 5 leads to an
increase of the affinity for the corresponding THP (4j, 4l) and
piperazine (4i, 4k) derivatives. The highest affinity is observed
for the 3,5-dimethyl derivative (4l), while the most important
increase is observed for the piperazine analogue (4k).
In parallel, the affinity of phthalimide derivatives (1a−l) is
also determined (Table 3), as some reports indicated a
biological effect of these compounds.11 Except for some
analogues, the affinity is weak as also reported separately for
compound 1a.12 Like for the other two groups of molecules, it
appears that the THP analogues (1b, 1d, 1f, 1h, 1j, 1l) have a
higher affinity than the corresponding piperazine analogues (1a,
1c, 1e, 1g, 1i, 1k). In THP series, the presence of a substituent
in position 4 of the distal phenyl ring has no or minimal impact
in terms of affinity, e.g., the unsubstituted derivatives (1b) and
the 4-chloro analogue (1f) have a similar affinity of 706 and 631
nM, respectively. However, the presence of two substituents in
positions 3 and 5 leads to an increase of affinity of 425 and 105
nM for the 3,5-difluoro analogue (1j) and the 3,5-dimethyl
analogue (1l), respectively. The 3,5-dimethyl derivatives are
four (1k) and seven (1l) times more potent on these receptor
sites in comparison with the unsubstituted analogue (1b).
a
compd
amine
R1
Ki
pKa
log P
3a
3b
3c
3d
3e
3f
piperazine
THP
H
24.7 3.6
6.1 0.9
7.21
8.06
7.15
8.02
7.12
7.98
7.41
8.38
7.06
7.90
7.55
8.43
4.42
4.95
4.66
4.96
5.23
5.53
4.84
5.32
4.86
5.1
H
piperazine
THP
4-F
4-F
54.3 6.9
33.5 18.5
50.7 14.9
42.5 11.8
221.4 19.3
31.6 5.1
28.95 3.2
7.29 1.07
21.0 1.7
8.06 0.35
piperazine
THP
4-Cl
4-Cl
3g
3h
3i
piperazine
THP
4-Me
4-Me
piperazine
THP
3,5-diF
3,5-diF
3,5-diMe
3,5-diMe
3j
3k
3l
piperazine
THP
4.34
5.82
a
Ki in nM; mean SEM n ≥ 3.
All naphthyl analogues possess a significant affinity for 5-
HT1A receptors. Except for halogenated analogues (3c−f), the
THP derivatives (3b, 3d, 3f, 3h, 3j, 3l) present a higher affinity
than the piperazine ones (3a, 3c, 3e, 3g, 3i, 3k). This increase is
approximately four times. In this series, the impact of the
substitution of the distal phenyl ring is limited except for the 4-
halogenated derivatives (3c−f) and the methyl derivatives (3g,
3h), which possess a lower affinity than the unsubstituted
derivatives (3a, 3b). For the 4-fluorine analogues (3c, 3d), the
electron-withdrawing effect of the fluorine on the electronic
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ACS Medicinal Chemistry Letters
Letter
172 85 nM for compound 4l. The inhibitory effect of all four
compounds was reversed by the simultaneous application of
WAY-100635 (100 nM). One experiment performed with
compound 4b is illustrated in the Supporting Information. The
six compounds thus behave as 5-HT1A agonists. The order of
potency, 4j > 4l > 4k > 4b > 4i > 4a, is in good agreement with
binding affinities obtained on cloned receptors.
The binding mode of the ligands with higher affinity (4k, 4l)
was explored by molecular docking simulations and compared
to that of the corresponding unsubstituted (4a, 4b) analogues
(for experimental details, see Supporting Information).
Four main interactions known to be important for the
receptor affinity16 are found for all the compounds (Figure 1).
Table 3. Affinity for 5-HT1A Receptors and Physicochemical
Characteristics of Phthalimide Derivatives (1a−l)
a
compd
amine
R1
Ki
82%
pKa
log P
1a
1b
1c
1d
1e
1f
piperazine
THP
H
6.81
7.66
6.74
7.61
6.71
7.57
7.01
7.98
6.66
7.50
7.15
8.03
3.47
3.99
3.69
3.99
4.26
4.56
3.87
4.35
3.89
4.13
4.37
4.85
H
706 119
80.4%
piperazine
THP
4-F
4-F
76.83%
97.36%
631 54
97%
piperazine
THP
4-Cl
4-Cl
1g
1h
1i
piperazine
THP
4-Me
4-Me
80%
piperazine
THP
3,5-diF
3,5-diF
3,5-diMe
3,5-diMe
79.56%
425 59
496 113
105 11
1j
1k
1l
piperazine
THP
a
Ki in nM; mean SEM n ≥ 3 (or for compounds with low affinity,
the screening value expressed in % of residual specific radioactivity at 1
μM is mentioned).
Besides the affinity, calculated pKa and lipophilicity have
been examined. Procedures used are indicated in the
Supporting Information section. The presence of a basic
nitrogen is an important element in terms of interactions with
such GPCR. Therefore, the hydrogen bond between an
aspartate in the binding pocket and this nitrogen is reinforced
when this nitrogen is charged. In all series, an increase of pKa
and lipophilicity is observed for the THP analogues in
comparison with the piperazine analogues (Tables 1−3).
Nevertheless, the affinity is not systematically increased in
parallel. Indeed, in the naphthyl series, the unsubstituted
analogues (3a, 3b) and the 3,5-dimethyl analogues (3k, 3l)
have a similar affinity, while physicochemical parameters are
increased for the substituted derivatives (3k, 3l). In the
quinoxaline series, the affinity is increased in parallel to the
physicochemical parameters when comparing piperazine and
THP analogues. Regarding the 3,5-difluoro analogues (4i, 4j),
the higher affinity is associated to a slightly reduced pKa value
and a higher lipophilicity parameter than the unsubstituted
analogues (4a, 4b), while for the 3,5-dimethyl analogues (4k,
4l) the highest affinity, pKa, and lipophilicity values are
observed in this series.
Complementary to binding studies, some electrophysiolog-
ical experiments were devoted to the determination of the
intrinsic activity of selected compounds (4a, 4b, 4i, 4j, 4k, 4l)
on the firing rate of presumed serotonergic neurons of the
dorsal raphe nucleus (DR) recorded on rat brain slices
according to previously reported procedures.13 Indeed, several
studies have shown that the firing of these neurons is inhibited
by 5-HT1A agonists such as 8-OH-DPAT.14 This effect is
blocked or reversed by 5-HT1A antagonists such as WAY-
100635.15 The six compounds tested induced a concentration-
dependent decrease in the firing rate of DR presumed
serotonergic neurons. Concentration−response curves are
illustrated in the Supporting Information. The IC50s were,
respectively, 1683 783 nM for compound 4a, 460 72 nM
for compound 4b, 1140 660 nM for compound 4i, 95 70
nM for compound 4j, 383 196 nM for compound 4k, and
Figure 1. Binding mode of compounds 4a, 4b, 4k, and 4l (C, N, O,
and H atoms in magenta, blue, red, and cyan, respectively) in a human
5-HT1A receptor agonist model. The hydrogen bonds are indicated by
yellow dashed lines.
The first key binding feature is the protonated amine, which
forms hydrogen bonds with Asp 116 (Asp 3.32 according to the
Ballesteros and Weinstein numbering),17 a specific residue for
ligand binding among all mammalian biogenic amine
receptors.18 Two other hydrogen bonds are also observed.
Indeed, a hydrogen bond is detected between the hydrogen
atom of the amide group and the hydroxyl group of Tyr 390
(Tyr 7.43). An interaction with this residue was also
demonstrated in the ligand binding of other aryl piperazine
derivatives.19 Then a bifurcated hydrogen bond is observed
between the carbonyl oxygen atom and the amide group of Asn
386 (Asn 7.39). This is consistent with site directed
mutagenesis data showing that the valine substitution for Asn
7.39 induces a reduction in the binding affinity of 5-HT1A
ligands.20
The last key binding feature is the distal phenyl ring
interacting with Phe 362 (Phe 6.52).2,19 Contrary to the
hydrogen bonds, the geometrical parameters of this interaction
are shown to be altered following the presence of a THP or a
piperazine group (Figure 1). Indeed, as suggested in previous
work,2 in the THP analogues (4b and 4l), the phenyl ring
preferentially adopts an almost coplanar orientation relative to
the THP moiety, which appears to be favorable for an edge-to-
face CH−π interaction with Phe 362. The dihedral angle
measured between the ring planes (86° and 91° for 4b and 4l,
respectively) is very close to the optimal value of 90°.21 In
contrast, for piperazine analogues, the perpendicular orientation
of the phenyl ring seems to be less favorable for the CH−π
interaction with dihedral angle values of 65° and 56° for 4a and
4k, respectively. This finding could be one of the keys for
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ACS Medicinal Chemistry Letters
Letter
explaining the different affinities observed between THP and
piperazine compounds.
character) and an increase of affinity when located in positions
3 and 5 in the quinoxaline series. Inductive and mesomeric
electronic effects of halogen atoms can be sometimes in
competition, and in these molecules, the mesomeric effect
increasing the electronic density of the phenyl ring could
explain the increase of affinity in comparison with the
unsubstituted analogue. Fluorine is also quite different than
other halogens as reported with the so-called σ-hole in the
context of halogen bonding.27 In case of a reduced affinity
would be wanted, but this is not the priority in this program,
other electron-withdrawing groups should be introduced taking
into account a possible deleterious sterical impact. In these
conditions, a trifluoromethyl group could be most appropriate.
In conclusion, substitution of the distal phenyl ring by two
electron-donating methyl groups has permitted to obtain the
highest increase of affinity for 5-HT1A receptors in both
naphthyl and quinoxaline series. This is also observed for the
intermediate phthalimide analogues. Although THP analogue
4l is the most potent, the most important impact of the current
strategy is observed with compound 4k compared to 4a.
Examining the affinity and the physicochemical parameters of
the corresponding compounds, the increase of affinity seems to
be related to the increase of electronic density on the distal
benzene ring. Finally, a possible extension of this work would
be the biological and theoretical evaluation on other receptors
to see whether the consequences of the current strategy can
also be observed.
The influence of 3,5-dimethyl substituent as an electron-
donating group is difficult to observe in the docking results. To
measure this impact, the electrostatic potential of each
compound was evaluated according to quantum calculations
(see Supporting Information for experimental details). The
presence of 3,5-dimethyl substituent appears to cause an
electron enrichment of the phenyl ring (Figure 2), which is
Figure 2. Electrostatic potential of compounds 4a (top left), 4b (top
right), 4k (bottom left), and 4l (bottom right). The electrostatic map
shows the electron-rich (purple) to the electron-deficient (red)
regions of the compounds.
favorable for an edge-to-face CH−π interaction with Phe 362.
However, another explanation can be considered for the
favorable impact of the substitution. This is the generation of
additional favorable interactions with the receptor, namely,
hydrophobic contacts between one methyl and the residue Val
117 (Val 3.33) (Figure 1). This residue is known to be also
important for the binding of 5-HT1A agonists.16
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details regarding synthesis, characterization of
compounds, in vitro binding procedure, electrophysiological
experiments, and molecular modeling studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
In the exploration of 5-HT1A receptor−ligand recognition,
several studies have been carried out,19,22,23 but no one, in our
knowledge, further examined the CH−π interaction described
in the current work. As the binding pocket of different GPCRs
presents some homology, it will be interesting in the
continuation of this work to evaluate this concept with other
targets. Nevertheless, although homology concerns some amino
acid residues are quite well conserved, the key residue Asn 7.39
is found to be replaced in other receptors (i.e., Val in 5-HT2A-5-
HT2CR; Phe in α1A-α2AR; Thr in D2-D4R). As mentioned
above, Val mutation in the sequence of 5-HT1A receptors20 has
shown a decrease of affinity for tested compounds. Moreover,
quinoxaline analogues previously described1 present low affinity
for α2A or D4 receptors. Otherwise, 1,2,3,6-tetrahydropyridine
moiety is used in the medicinal chemistry field24 as
reviewed,25,26 although some health hazards are observed
with MPTP analogues.25 Because these compounds are
structurally related to MPTP, they could be tested in the
context of a structure−toxicity relationship.
In the present work, a significant increase of affinity is
observed when electron-donating groups are present in the
distal benzene ring (compound 4l) leading to a possible
reinforcement of the interaction observed in docking studies
and previously seen with the unsubstituted analogue 4b from a
conformational analysis.2 A favorable impact of the lipophilicity
and pKa of the compound cannot be excluded, but the
corresponding naphthyl analogue 3l has a lower affinity despite
a higher lipophilicity and pKa. In the present work, the presence
of the electronegative fluorine leads to a reduced affinity when
located in position 4 (related to its electron-withdrawing
AUTHOR INFORMATION
Corresponding Author
*(J.-F.L.) Phone: 00 32 43 66 43 77. Fax: 00 32 43 66 43 62. E-
mail: JF.Liegeois@ulg.ac.be.
■
Funding
Supported in part by grants of the F.R.S.-FNRS (Belgium) and
the Fonds Spec
Liege (Belgium).
Notes
́
iaux pour la Recherche of the University of
̀
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The technical assistance of S. Counerotte, J. Widart, C.
Gillissen, and L. Massotte for elemental analyses, mass spectra,
in vitro binding experiments, and electrophysiological record-
ings, respectively, is gratefully acknowledged. J.-F.L. is Research
Director of the F.R.S.-FNRS. S.D. was supported financially by
a postdoctoral fellowship of the F.R.S.-FNRS and a collective
grant of the University of Lieg
̀
e.
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