Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors

Article abstract of DOI:10.1016/j.bmcl.2014.03.043

This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT _2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure-activity relationship of this series of compounds is presented herein.

Full text of DOI:10.1016/j.bmcl.2014.03.043

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2118–2122
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design of novel multiple-acting ligands towards SERT and 5-HT2C
receptors
⇑
}
Olivér Éliás , Éva Ágai-Csongor, György Domány, György Miklós Keseru, Anikó Gere, Béla Kiss,
Éva Hellinger, Mónika Vastag, István Gyertyán
Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake
transporter inhibitor and serotonin 5-HT2C receptor antagonist properties. A novel series of 1,3-diphe-
nylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and
in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound.
The synthesis and structure–activity relationship of this series of compounds is presented herein.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 February 2014
Revised 12 March 2014
Accepted 14 March 2014
Available online 24 March 2014
Keywords:
Designed multiple ligands
SERT inhibitor
5-HT2C antagonist
According to the contemporary network theory of affective
disorders, multiple weak interventions may be more effective in
modifying an abnormally functioning system than a robust single
point action. Thus, within pharmacotherapy a designed multiple
ligands (DML) strategy seems to offer the best chance for improved
efficacy against core and comorbid symptoms of depression.1
Serotonin re-uptake transporter (SERT) inhibition is a mecha-
nism with proven antidepressant efficacy, though with certain
side-effects (e.g., acute anxiogenesis, insomnia, sexual dysfunction)
and slow onset of action. Pharmacological knowledge on the 5-HT2C
receptor suggested that its antagonism as an added mechanism to
SERT inhibition may confer a faster onset of action, improvements
in certain co-morbid symptoms (anxiety, perturbed sleep, sexual
dysfunction) and diminished occurrence of the above mentioned
side-effects.2a
a suitable template for this purpose.3 (Fig. 1) According to the
literature, substituents on the phenyl rings of fluoxetine analogues,
especially at para positions, are generally tolerated.4 Therefore, we
proposed coupling the 5-HT2C motif at this position. Furthermore, it
was understood that fluoxetine congeners with dimethylamino
groups instead of methylamino have similar affinities towards
SERT. Hence, it was decided that only compounds with the
dimethylamino moiety would be prepared in order to expedite
chemical synthesis.
Instead of the notion of simply linking or joining pharmaco-
phores, a more attractive merging strategy was applied. The
CH3
N
O
A knowledge-based pharmacophore hybridisation approach has
been applied to elaborate compounds possessing dual activity
towards SERT and the 5-HT2C receptor. Our aim was to reach the
low nanomolar region concerning binding affinities while
maintaining druglike properties.
N
CH3
NH
NH
NH
2
O
SB-200646A
Fluoxetine (1) was selected as one of our starting points due to,
at least in part, its inherent affinity toward aminergic receptors,
apparently indicating that there is an overlap between the two
pharmacophores.2b The biaryl urea scaffold of GSK (SB-200646A)
served as a 5-HT2C motif and RO-60-0491 was also considered as
CF3
O
1
N
NH
NH
Fluoxetine
3
RO-60-0491
⇑
Corresponding author. Tel.: +36 0618898731.
E-mail address: elias@richter.hu (O. Éliás).
Figure 1. Fluoxetine and 5-HT2C templates (for binding affinities see Table 1).
http://dx.doi.org/10.1016/j.bmcl.2014.03.043
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

O. Éliás et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2118–2122
2119
Table 1
phenoxy ring of fluoxetine and the pyridine ring in SB-200646A had
obviously been identified as shared elements of the pharmaco-
phores capable of being the common backbone of the single
template framework.
Synthesis and binding affinities for compounds 8a–f and binding affinities for the
reference compounds
CH3
CH3
Thus, elaboration of the urea linker at the 4 position of the
phenoxy ring of fluoxetine seemed to be plausible. To that end,
2-hydroxy-5-nitropyridine was first chosen as an acidic pronucle-
ophile in the Mitsunobu etherification step of the facile straightfor-
ward synthetic route5 towards the biarylureas planned (see
Scheme 1). Nitro derivatives were in turn converted into anilines.
Ureas were then synthesized via isocyanates generated in situ from
the aniline reaction partner and triphosgene in dichloromethane or
from the corresponding carboxylic acid in the presence of diphenyl
phosphorazidate and diisopropylethylamine in acetonitrile.
Disappointingly, the 8a–c pyridine compounds prepared thus
proved to be totally inactive in both assay systems.7 However,
encouragingly, omission of the pyridine nitrogen atom led us to
compounds 8d–f that exhibited remarkable affinities towards our
targets (see Table 1).
Next, we decided to elaborate compound 9a as a structural iso-
mer of 8d starting from the corresponding meta substituted nitro-
phenol (see Table 2). As a result of this modification 5-HT2C affinity
dropped dramatically. The same tendency was observed in the case
of the 9b naphthalen-2-yl derivatives. Thus, evolving the para
substituted compound family was underpinned by affinity data ac-
quired from these experiments.
N
N
CH3
CH3
O
X
O
X
O
R
NH2
NH
NH
7a-b
8a-f
Compds
R
X
SERT
5-HT2C
8a
8b
8c
8d
8e
8f
1-Methyl-1H-indol-5-yl
1-Methyl-1H-indol-6-yl
Naphthalen-2-yl
1-Methyl-1H-indol-5-yl
1-Methyl-1H-indol-6-yl
Naphthalen-2-yl
N
N
N
C
C
C
À5%
1%
3%
7%
15%
43%
15.9
10.9
1.7
109
124
6.2
9.0
19.3
62.0
5.6
Fluoxetine
SB-200646A
Ro-60-0491
>10,000
>10,000
Reagents and conditions: from 7a to 8a–c, from 7b to 8d–f, and the corresponding
carboxylic acid,6 diphenylphosphoryl azide, N,N-diisopropylethylamine, acetoni-
trile, 80 °C, 6 h. Values are binding Ki in nM or percentage inhibition of radioligand
binding at a compound concentration of 300 and 1000 nM for SERT and 5-HT2C
,
respectively.7
Early results revealed that low metabolic stability and poor
penetration seemed to be the main issue to be dealt with in con-
nection with the compound family, for example compound 8d:
Table 2
Structure and binding affinities for compounds 9a–b
Clint in human and mouse liver microsomes:8 2.66 and 3.25 mL/
9
CH3
N
CH3
N
min g liver, respectively; PappA-B
:
5.8 Â 10À6 cm/s, efflux ratio:9
CH3
NH2
CH3
NH
O
O
NH
R
R1
O
CH3
HO
i
N
+
CH3
X
9a-b
SERT
7c
R2
OH
R3
Compds
R
5-HT2C
4
9a
9b
1-Methyl-1H-indol-5-yl
Naphthalen-2-yl
9.4
28.2
652
87.6
5a-e
Reagents and conditions: corresponding carboxylic acid,6 diphenylphosphoryl
azide, N,N-diisopropylethylamine, acetonitrile, 80 °C, 6 h. Values are binding Ki in
CH3
CH3
N
nM.
N
CH3
CH3
ii
O
X
R3
O
X
R3
5.3. The human metabolic stability of 8f naphthalen-2-yl derivative
omitting the indol N-methyl group was only moderate thus far
(Clint in human and mouse liver microsomes: 1.38 and 0.03 mL/
min g liver, respectively). On the other hand, while physico-chem-
ical parameters were satisfactory Pgp liability turned out to be an
important factor concerning poor penetrability (see efflux ratio
above). It was reasoned that replacement of the indol moiety with
other appropriately substituted heterocycles or simpler phenyl
groups having a suitable substitution pattern together with adjust-
ment to the hydrogen bond donor properties might help improve
brain exposure.
Having these aims in mind, further analogues were planned and
synthesised (see Table 3). First, compound 8g the N-ethyl indol
analogue of 8d was prepared. While binding activity and penetra-
tion properties remained in the same range (SERT Ki: 37.9 nM,
5-HT2C Ki: 10.7 nM) only slightly improved metabolic stability
was observed (Clint in human and mouse liver microsomes: 2.04
and 2.84 mL/min g liver, respectively). Incorporation of hetero-
bicyclic motifs for example the imidazo[1,2-a]pyridin-6-yl group
R1
R2
R1
R2
7a-e
6a-e
R1
H
H
R2
NO2
NO2
H
NO2
H
NH2
NH2
H
R3
H
H
NO2
H
NO2
H
H
NH2
H
NH2
X
N
C
C
C
C
N
C
C
C
C
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
H
OMe
OMe
H
H
H
OMe
OMe
NH2
H
Scheme 1. Reagents and conditions: (i) triphenylphosphine, diisopropyl azodicar-
boxylate, dichloromethane, ambient temperature, 48 h; (ii) PtO2/H2, ethanol.

2120
O. Éliás et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2118–2122
Table 3
Table 5
Structure and binding affinities for compounds 8g–o
Structure and binding affinities for compounds 12–14
CH3
CH3
N
CH3
N
CH3
N
N
CH3
CH3
CH3
CH3
O
O
O
O
Cl
Cl
O
R
NH2
NH2
NH
NH
Q
7b
12-14
SERT
7b
8g-o
SERT
Compds
Q
5-HT2C
Compds
R
5-HT2C
8g
8h
8i
8j
8k
8l
8m
8n
8o
1-Ethyl-1H-indol-5-yl
Imidazo[1,2-a]pyridin-6-yl
3,4-diCl-Ph
3-Cl-4-Me-Ph
3-I-4-Me-Ph
3-Cl-4-MeO-Ph
3-CF3-4-MeO-Ph
3-CF3-4-MeS-Ph
3-OMe-4-Cl-Ph
37.9
4.0
10.7
53%
2.9
3.0
2.4
11.2
3.3
3.4
O
O
12
65.3
89.6
57.1
78.9
135.0
61.4
121.0
41.1
96.4
31%
NH
NH
13
14
N
CH3
31.0
16.3
O
Reagents and conditions: 8g–h: from the corresponding carboxylic acid,5 diphen-
ylphosphoryl azide, N,N-diisopropylethylamine, acetonitrile, 80 °C, 6 h; to 8i–o:
from the corresponding aniline,6 triphosgene, triethylamine, dichloromethane,
ambient temperature, 1 h. Values are binding Ki in nM or percentage inhibition of
radioligand binding at a compound concentration of 300 and 1000 nM for SERT and
5-HT2C, respectively.
102.0
10.2
N
N
Reagents and conditions: to 12: 3,4-dichlorobenzoic acid, l-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide, 1-hydroxybenzotriazole, dimethylformamide, ambient
temperature, 12 h; to 13: 3,4-dichloro-N-methylaniline, triphosgene, triethylamine,
dichloromethane, ambient temperature, 1 h; to 14: from 2-[(-3,4-dichloro-
phenyl)amino]ethanol according to the procedure described in literature.10a Values
are binding Ki in nM.
O
Cl
N
O
O
Cl
the in vitro screen criteria (Clint in human and mouse liver
H3C
microsomes: 0.68 and 1.25 mL/min g liver, respectively; PappA-B
:
N
N
7.5 Â 10À6 cm/s, efflux ratio: 2.2) although its penetration was still
suboptimal in terms of either PappA-B value or efflux ratio.
Figure 2. Structure of compound 10.
Whereas, 5-HT2C competitor molecules, represented by
compound 10 (see Fig. 2),10 contain two ether oxygen atoms in
an adjacent position to each other, according to the pharmaco-
phore model disclosed11 the one which is incorporated into an
alkylpiperidine side chain seemed to be unnecessary regarding
5-HT2C binding. Noteworthy, H-bond acceptor functionality, in
the form of a methoxy group being always in para position to the
urea nitrogen, might be beneficial for achieving low 5-HT2C affinity.
To investigate the role of the alkoxy functions we synthesized
further methoxy containing derivatives (see Table 4). In the case
of compound 11a 5-HT2C affinity remained in the same range but
afforded derivatives having affinity towards only SERT (see 8h in
Table 3).
Furthermore, various disubstituted (e.g., methyl, halogen,
methoxy) phenyl groups were introduced at the para position
utilizing the urea linker. In this set of analogues 5-HT2C affinity is
far more pronounced than SERT affinity. The dual acting isomeric
compounds (8l and 8o) were obtained by applying the 3(4)-
chloro-4(3)-methoxy substitution pattern. Compound 8l met
Table 4
Structure and binding affinities for compounds 11a–b
CH3
CH3
N
N
CH3
CH3
O
O
R2
O
O
R2
H3C
H
3C
R1
R1
Compds
R1
R2
H
SERT (%)
38
5-HT2C
2.8
NH
NH
Cl
11a
O
Cl
NH
NH
Cl
Cl
11b
H
À9
197
O
Reagents and conditions: corresponding aniline,6 triphosgene, triethylamine, dichloromethane, ambient temperature, 1 h. Values are binding Ki in nM or percentage
inhibition of radioligand binding at a compound concentration of 300 and 1000 nM for SERT and 5-HT2C, respectively.

O. Éliás et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2118–2122
2121
activity, while 5-HT2C activity slightly decreased. Nevertheless,
two well balanced compounds 12 and 16a were identified among
the class having affinities definitely under the screening limits.
Moreover, both compounds achieved good metabolic stability and
had acceptable penetrability (for 12: Clint in human and mouse liver
CH3
N
CH3
Cl
O
O
CH3
microsomes: 0.65 and 1.52 mL/min g liver, respectively; PappA-B
:
NH
N
11.3 x 10À6 cm/s, efflux ratio: 1.1; for 16a: Clint in human and
mouse liver microsomes: 0.59 and 1.93 mL/min g liver, respec-
tively; PappA-B: 19.9 x 10À6 cm/s, efflux ratio: 0.7).
Figure 3. Structure of compound 15.
In summary, combination of the mentioned scaffolds led to
promising hits. During the lead finding phase an embryonic struc-
ture–activity relationship was also established. Since the identifi-
cation of the first dually acting compound our original idea has
now evolved into a developable compound family possessing a dif-
ferent and unique binding profile. The 16a carboxamide derivative
is currently undergoing further evaluation and a more detailed ac-
count of its optimisation and pharmacology will be published
elsewhere.
Table 6
Synthesis and binding affinities for compounds 16a–c
CH3
CH3
N
N
CH3
CH3
O
O
O
NH2
NH
R
Acknowledgment
7b
16a-c
The authors thank Ákos Tarcsay for helpful discussions. O.É. is
indebted to Noémi Bús for preparative assistance.
Compds
R
SERT
5-HT2C
16a
16b
16c
3-Cl-4-Me-Ph
3-Cl-4-MeO-Ph
3-CF3-4-MeO-Ph
34.6
15.9
22.3
45.3
152.0
90.6
References and notes
1. (a) Roth, B. L.; Sheffler, D. J.; Kroeze, W. K. Nat. Rev. Drug Disc. 2004, 3, 353; (b)
Csermely, P.; Ágoston, V.; Pongor, S. Trends Pharmacol. Sci. 2005, 26, 178; (c)
Morphy, R.; Rankovic, Z. J. Med. Chem. 2005, 48, 6523; (d) Millan, M. J.
Neurotherapeutics 2009, 6, 53.
Reagents and conditions: corresponding carboxylic acid,5 l-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide, 1-hydroxybenzotriazole, dimethylformamide, ambient
temperature, 12 h. Values are binding Ki in nM.
2. (a) Millan, M. J. Pharmacol. Ther. 2006, 110, 135; (b) For binding affinities of
Fluoxetine toward some aminergic receptors see Table 2 in Ref. 2a.
3. Forbes, I. T.; Kennett, G. A.; Gadre, A.; Ham, P.; Hayward, C. J.; Martin, R. T.;
Thompson, M.; Wood, M. D.; Baxter, G. S.; Glen, A.; Murphy, O. E.; Stewart, B.
A.; Blackburn, T. P. J. Med. Chem. 1993, 36, 1104.
4. Dually acting compounds towards SERT and histamine H3 receptor were
detailed in Stocking, E. M.; Miller, J. M.; Barbier, A. J.; Wilson, S. J.; Boggs, J. D.;
McAllister, H. M.; Wu, J.; Lovenberg, T. W.; Carruthers, N. I.; Wolin, R. L. Bioorg.
Med. Chem. Lett. 2007, 17, 3130.
5. Intermediate 3-(dimethylamino)-1-phenylpropan-1-ol can be readily obtained
by reduction of the appropriate Mannich ketone with sodium borohydride in
methanol. Mitsunobu reaction of the thus obtained alcohol with the
corresponding nitrophenol followed by catalytic reduction of the nitro
derivative furnished the desired amino intermediates: (a)Molloy, B. B.;
Schmiegel, K. K. U.S. Patent 4,314,081, 1982.; (b) Srebnik, M.; Ramachandran,
P. V.; Brown, H. C. J. Org. Chem. 1988, 53, 2916.
SERT affinity considerably dropped. The isomeric substitution
pattern in compound 11b proved to be detrimental to both of
our targets.
Subsequently, using some further 3,4-dichloro substituted
building blocks, another set of novel compounds containing differ-
ent linkers was elaborated (see Table 5). By reducing the hydrogen
bond donor (HBD) capacity, all of the mentioned modifications
were particularly aimed at reducing Pgp liability. According to
our expectation, elimination of one of the NH function via alkyl-
ation or applying an NHCO linker resulted in derivatives having
diminished affinity toward efflux proteins (efflux ratio: 1.1 and
1.6 for compounds 12 and 13, respectively). Encouragingly, intro-
duction of the imidazolidinone linker in 14 did not affect binding
properties while it reduced HBD capacity to 1 compared to com-
pound 8i.
In addition, compound 15 (see Fig. 3) a conformationally more
restricted analogue of 8j incorporating one of the urea nitrogen
atoms into a five membered heterocycle condensed to the phenyl
ring was synthesised.12 While SERT activity remained in the
same region, 5-HT2C activity considerably improved reaching the
subnanomolar range (SERT Ki: 69.5 nM, 5-HT2C Ki: 0.6 nM).
Improved metabolic stability was also observed (Clint in human
and mouse liver microsomes: 0.06 and 0.90 mL/min g liver, respec-
tively). Of these modifications, the carboxamide linker containing
derivative 12 deserved further attention due to its remarkably
improved penetrability properties and good human metabolic
stability. Carboxamides were elaborated via an amide coupling
sequence from carboxylic acids using l-ethyl-3-(3-dimethylamino-
propyl)carbodiimide and 1-hydroxybenzotriazole as additives in
dimethylformamide.
6. Commercially available.
7. SERT binding was determined according to the method described in (a)
D’Amato, R. J.; Largent, B. L.; Snowman, A. M.; Snyder, S. H. J. Pharmacol. Exp.
Ther. 1987, 242, 364. Male Sprague–Dawley rats weighing 180–220 g were
used. Membrane was prepared from rat whole brain except cerebellum and
pons-medulla. 0.2 mL membrane suspension (containing ꢀ0.12 mg protein)
was incubated with 1 nM [3H]citalopram in the presence or absence of
compounds (9–10 concentrations ranging for 10
temperature. Final incubation volume was 0.25 ml. Non-specific binding,
assessed in the presence of paroxetine (0.5 M) was 2–4% of the total
lM to 0.1 nM) for 1 h at room
l
binding. The assay was stopped by filtration on Unifilter-96 GF/B filter
(pretreated with 0.5% polyethyleneimine). The filters were washed 3 times
with 1 ml of ice-cold buffer and radioactivity of the filters were counted by
liquid scintillation spectrometry in 40 lL MicroScintTM-20 scintillation
cocktail using a TopCount NXTTM microplate scintillation & luminescence
counter; 5-HT2C binding was determined according to the method described in
(b) Pandey, S. C.; Dubey, M. P.; Piano, M. R.; Schwertz, D. W.; Davis, J. M.;
Pandey, G. N. Eur. J. Pharmacol. – Mol. Pharmacol. 1993, 247, 81. Male Sprague–
Dawley rats weighing 180–220 g were used. Membrane was prepared from rat
choroid plexus. 0.4 mL membrane suspension (containing 22–25
was incubated with 1 nM [3H]mesulergine in the presence or absence of
compounds (9–10 concentrations ranging for 10 M to 0.1 nM) for 30 min at
37 °C. Final incubation volume was 0.5 mL. Non-specific binding, assessed in
the presence of mianserin (1
lg protein)
l
l
M) was ꢀ10% of the total binding. The assay was
terminated by filtration on Unifilter-96 GF/B filter (pre-soaked in 0.05%
polyethyleneimine). The filters were washed 3 times with 1 mL of ice-cold
buffer and radioactivity of the filters were counted by liquid scintillation
spectrometry in 40 lL MicroScintTM-20 scintillation cocktail using a TopCount
NXTTM microplate scintillation & luminescence counter.
8. In vitro metabolic stability was assessed using human (Xenotech, USA) and
We therefore focused on carboxamides as modified linker
containing derivatives and some analogues having the most
promising substitution patterns were next prepared using the same
protocol (see Table 6). Generally, this modification favoured SERT
NMRI mouse liver microsomes. Test compounds at 2.5
lM initial nominal
concentration were incubated for various lengths of time (0–20 min) with the

2122
O. Éliás et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2118–2122
liver microsomes. In vitro intrinsic clearance (Clint mL/min g liver) was
11. Micheli, F.; Pasquarello, A.; Tedesco, G.; Hamprecht, D.; Bonanomi, G.;
Checchia, A.; Jaxa-Chamiec, A.; Damiani, F.; Davalli, S.; Donati, D.; Gallotti,
C.; Petrone, M.; Rinaldi, M.; Riley, G.; Terreni, S.; Wood, M. Bioorg. Med. Chem.
Lett. 2006, 16, 3906.
calculated using the basic concept of clearance prediction (Rane, A.;
Wilkinson, G. R.; Shand, D. G. J. Pharmacol. Exp. Ther. 1977, 200, 420.)
according the following equations: Clint = Vmax/KM or if S << KM Clint = V/S;
Vmax = maximal rate of enzyme reaction; KM = affinity constant of substrate;
S = substrate concentration; V = actual rate of enzyme reaction under first
order conditions.
12. The condensed 5-HT2C antagonist motif derived from SB-242084; medicinal
chemistry efforts detailed in (a) Bromidge, S. M.; Duckworth, M.; Forbes, I. T.;
Ham, P.; King, F. D.; Thewlis, K. M.; Blaney, F. E.; Naylor, C. B.; Blackburn, T. P.;
Kennett, G. A.; Wood, M. D.; Clarke, S. E. J. Med. Chem. 1997, 40, 3494;
compound 15 was synthesised from 7b and the corresponding amine obtained
according to the procedure described in (b) Bromidge, S. M.; Dabbs, S.; Davies,
D. T.; Davies, S.; Duckworth, D. M.; Forbes, I. T.; Gaster, L. M.; Ham, P.; Jones, G.
E.; King, F. D.; Mulholland, K. R.; Saunders, D. V.; Wyman, P. A.; Blaney, F. E.;
Clarke, S. E.; Blackburn, T. P.; Holland, V.; Kennett, G. A.; Lightowler, S.;
Middlemiss, D. N.; Trail, B.; Riley, G. J.; Wood, M. D. J. Med. Chem. 2000, 43,
1123.
9. Permeability (PappA-B) and efflux ratio (PappB-A/PappA-B) were measured using
VB-Caco-2 (vinblastine-treated Caco-2) cells in 3–50 lM as described in
Hellinger, É.; Bakk, M. L.; Pócza, P.; Tihanyi, K.; Vastag, M. Eur. J. Pharm. Sci.
2010, 41, 96.
10. (a) Goodacre, C. J.; Bromidge, S. M.; Clapham, C.; King, F. D.; Lovell, P. J.; Allen,
M.; Campbell, L. P.; Holland, V.; Riley, G. J.; Starr, K. R.; Trail, B. K.; Wood, M. D.
Bioorg. Med. Chem. Lett. 2005, 15, 4989; (b) for the binding affinity of compound
10 toward 5-HT2 receptors see Table 1 in Ref. 10a.