Identification of novel indanylsulfonamide guanylhydrazones as potent 5-HT6 serotonin receptor antagonists

Article abstract of DOI:10.1021/jm900796p

Changing the N,N-(dimethylamino)ethyl side chain in the N-[3-(aminoethyl)inden-5-yl]sulfonamide 5-HT₆ serotonin receptor agonists 1 by a conformationally rigid guanylhydrazone moiety at the indene 3-position led to the identification of the tit

Full text of DOI:10.1021/jm900796p

J. Med. Chem. 2009, 52, 6153–6157 6153
DOI: 10.1021/jm900796p
Identification of Novel Indanylsulfonamide Guanylhydrazones as Potent 5-HT6
Serotonin Receptor Antagonists
†
†
‡
‡
Neus Mesquida,*,† Sara Lopez-Perez, Immaculada Dinares, Jordi Frigola, Ramon Merce, Jorg Holenz,
ꢀ
Raquel Perez, Javier Burgueno, and Ermitas Alcalde*
ꢀ
ꢁ
ꢁ ‡
€
‡
‡
,†
ꢀ
~
†
´
ꢁ
´
ꢁ
Laboratori de Quımica Organica, Departament de Farmacologia i Quımica Terapeutica, Facultat de Farmacia, Universitat de Barcelona,
ꢁ
Avda. Joan XXIII s/n, 08028 Barcelona, Spain, and ‡ESTEVE, Av. Mare de Deꢀu de Montserrat 221, 08041 Barcelona, Spain
Received June 3, 2009
Changing the N,N-(dimethylamino)ethyl side chain in the N-[3-(aminoethyl)inden-5-yl]sulfonamide
5-HT6 serotonin receptor agonists 1 by a conformationally rigid guanylhydrazone moiety at the indene
3-position led to the identification of the title indanylguanylhydrazones 6, which exhibited excellent
binding affinities and an antagonistic response at the 5-HT6 receptor, with Ki and IC50 values in the
nanomolar range (Ki g1.2 nM, IC50 g 47 nM, and Imax e 173%).
Introduction
moiety led to the title indanylguanylhydrazone sulfonamides
6, which showed a high binding affinity with Ki values g
1.2 nM and acted as 5-HT6 receptor antagonists.
The 5-HT6 serotonin receptor, one of the most recent
incorporations to the serotonin receptor family, was isolated
from rat striatal messenger ribonucleic acid (mRNAa) in 1993
and then identified in humans.1-3 It is one of the G protein-
coupled receptors (GPCRs), and its activation leads to an
increase in cyclic adenosine monophosphate (cAMP) produc-
tion.2,4,5 In the past few years, the 5-HT6 receptor has became
a promising therapeutic target with clinicalinterest, andrecent
research has developed a broad array of small molecules
acting as potent and selective 5-HT6 antagonists. However,
agonists have proved elusive because of their generally modest
selectivity.6-10
By developing an indole-to-indene switch in the quest for
5-HT6 ligands,11-13 we have been able to examine several sets
of indene-based sulfonamides, the N-[3-(aminoethyl)inden-
5-yl]sulfonamides 1 and the conformationally rigid counter-
parts 2, which show binding affinities with Ki values g3 nM
(Figure 1). Representative examples of 1-type ligands are the
N-(inden-5-yl)imidazothiazole-5-sulfonamides 3 and 4, which
have high affinities and function as potent full agonists for
In parallel, aminoguanidine hydrazones, displaying inter-
esting pharmaceutical profiles, are suitable structural motifs
in a variety of biological agents such as antitumorals,14,15
antiparasitics,16 enzyme inhibitors, e.g., 4-amidinoindanone
guanylhydrazone (AIGH),17 cardiotonics,15a,18 5-HT2A re-
ceptor antagonists (arylguanylhydrazones),19 and others
including those identified by the high throughput screening
(HTS) technology.20 A significant biological response of the
guanylhydrazone moiety is its mimicry of the aminoethyl
functionality of serotonin (5-HT). In 1995, Mattes and co-
workers designed the indolecarbaldehyde guanylhydrazone 7,
which emerged as the prototype of a new class of potent and
selective 5-HT4 receptor agonists 8 (Figure 2).21,22 Recently,
Cole et al. examined different indolecarbaldehyde(alkylke-
tone) guanylhydrazones 9 and 10 bearing a sulfonamide
group at the indole 5- or 1-position, which exhibited a high
binding affinity for the 5-HT6 receptor, e.g. 11, 12 (Ki =
1.0 nM) and 13, 14 (Ki e 8.0 nM), respectively.23,24 These
indolylsulfonamides, 9 and 10, are guanylhydrazone counter-
parts of the known arylsulfonyltryptamines exemplified by
the agonists 15 (E-6801)25 and 16 (WAY-181187).23,26
Chemistry. Several selected examples of 6-type indanyl-
sulfonamide were synthesized from suitable indanones
following the multistep procedures shown in Schemes 1
and 2. Preparation of the guanylhydrazone derivatives
started with the sulfonylation of aminoindanone 17 with
the appropriate sulfonyl chlorides, giving the corresponding
indanone sulfonamides 1811 and 19. Applying the same
experimental protocol, reaction of aminoindanones 17, 20,
23, and 25 with 6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfo-
nyl chloride afforded indanones sulfonamides 21, 22, 24, and
26, respectively. Moreover, reduction of nitroindanone 2712
afforded aminoindanone 28, which upon sulfonylation gave
indanone imidazothiazolesulfonamide 29. On the other
hand, N-alkylation of 21 provided N-methyl-N-indenylsul-
fonamide 30 (Scheme 1).
the 5-HT6 receptor (Ki g 4.5 nM, Emax g 98%, EC50
g
0.3 nM).11-13 An example of a 2-type ligand is the pyrrolidine
analogue 5, which exhibited a high binding affinity (Ki = 3 (
0.3 nM) although with moderate antagonist potency at micro-
molar level13 (Figure 1). Continuing our search for 5-HT6
serotonin receptor ligands, the aim of the present study was to
investigate a structural change in the basic amine moiety atthe
indene 3-position of indenylsulfonamides 1 and 2. The repla-
cement of the conformationally flexible N,N-aminoethyl or
the rigid cyclic amine side arm by the rigid guanylhydrazone
*To whom correspondence should be addressed. Phone: þ34 93
4024540 (E.A.). E-mail: ealcalde@ub.edu (E.A.); neusmesquida@
ub.edu (N.M.).
a Abbreviations: 5-HT, serotonin; mRNA, messenger ribonucleic
acid; GPCRs, G protein-coupled receptors cAMP, cyclic adenosine
monophosphate; AIGH, 4-amidinoindanone guanylhydrazone; HTS,
high throughput screening; SERT, serotonin transporter; HEK, human
embryo kidney; HTRF, homogeneous time-resolved fluorescence;
[3H]-LSD, tritiated lysergic acid diethylamide.
r
2009 American Chemical Society
Published on Web 09/09/2009
pubs.acs.org/jmc

6154 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19
Mesquida et al.
Figure 1. Indene-based frameworks targeting the 5-HT6 serotonin
receptor.
Figure 2. Indole guanylhydrazones and the 5-HT serotonin receptor
family: (a) 5-HT4 prototype 7 and 8-type ligands; (b) 5-HT6 indolyl-
sulfonamide guanylhydrazones 9 and 10, e.g. 11-14; (c) 5-HT6
arylsulfonyltryptamine counterparts represented by agonists 15 and 16.
The targeted indanylguanylhydrazone sulfonamides were
prepared by reaction between the corresponding indanone
sulfonamides and the appropriate hydrazine derivatives
under acidic conditions. Therefore, condensation of sulfo-
namides 18 and 19 with a suspension of aminoguanidine
hydrochloride, the latter prepared in turn from a suspension
of aminoguanidine bicarbonate and an excess of hydrochlo-
ric acid, provided indanylsulfonamide guanylhydrazones 31
and 32, respectively. Furthermore, reaction of compound 19
with 2-hydrazino-2-imidazoline hydrobromide in refluxing
ethanol/HCl gave the cyclic indanylguanylhydrazone sulf-
onamide 33 (Scheme 2 and Scheme S1 of SI).
Results and Discussion
An array of N-[3-(aminoethyl)inden-5-yl]sulfonamides 1
have been previously reported as part of our research work
on indene-based ligands for the 5-HT6 receptor, including the
potent agonists 4 and 5.11-13 Having substituted the N,
N-(dimethylamino)ethyl side chain in sulfonamides 1 by a
guanylhydrazone moiety, we focused our attention to exam-
ples of 6-type sulfonamide guanylhydrazones27 and the tar-
geted compounds 31-41 were selected on the basis of
previously established structural requirements for enhancing
the affinity of indene-based scaffolds toward the 5-HT6
receptor, especially the aryl(heteroaryl)portion of the sulfon-
amide functionality (e.g., the 6-chloroimidazo[2,1-b]thiazole
motif).11,12 Selected indanylsulfonamide guanylhydrazones
31-41 were tested in a standard radioligand competition
binding assay,28 using membranes of human embryo kidney
cells (HEK-293) expressing the human 5-HT6 recombi-
nant receptor, and were found to exhibit affinities with Ki
values g1.2 nM (Table 1). The substitution of a 2-naphthyl
nucleus in 31 (Ki = 62 ( 29 nM) by a 4-methyl-3,4-dihydro-
2H-1,4-benzoxazine motif lowered the Ki value to 26 nM for
compound 32. However, conversion of the guanylhydrazone
group to the imidazolinylhydrazone 33 resulted in a ∼3-fold
loss in activity relative to 32.
Following the same experimental procedure, condensation
of indanone imidazothiazolesulfonamides 21, 22, 24, 26, 29,
and 30 with aminoguanidine hydrochloride afforded indanyl-
sulfonamide guanylhydrazones 34, the racemic 35, and
36-39, respectively. Finally, reaction of compounds 21 and
29 with 2-hydrazino-2-imidazoline hydrobromide in refluxing
EtOH/HCl provided cyclic indanylguanylhydrazone sulfona-
mides 40 and 41, respectively (Scheme 2 and Scheme S1 of SI).
Pure indanylguanylhydrazone sulfonamides were isolated
as solids after crushing the evaporated reaction mixture with a
suitable solvent. The structure of the new compounds was
confirmed by spectroscopic methods. Their 1H NMR and 13
C
NMR chemical shifts and physical data are gathered in the
Experimental Section (see Table 1 and Supporting Informa-
tion (SI)). The 1H NMR spectra of guanylhydrazone hydro-
chlorides 31, 32, and 34-39 recorded in DMSO-d6 at 300 MHz
are in agreement with the assigned structures: for the guanyl-
hydrazone moiety, a singlet at ∼11 ppm corresponding to one
NH group, and a broad signal at ∼8 ppm, corresponding to the
guanyl group. Moreover, on the basis of a 1D NOESY
experiment at 500 MHz in DMSO-d6, it was inferred that the
CdN- bond of 35 belonged to an E-isomer structure because
irradiation of the methyl group led to an enhancement of
both dN-NH- and -CH2- (Figure S1, SI).
The affinity was enhanced upon introduction of the
6-chloroimidazo[2,1-b][1,3]thiazole structural motif, with com-
pounds 34 (Ki = 1.2 ( 0.6 nM) and the racemic 35 (Ki = 1.6 (
0.1 nM) exhibiting the best binding affinities at the 5-HT6
receptor. Moving the sulfonamide group from the indane
6-position to the 5-position hardly changed the binding affinity.
Comparing the affinities of the isomers 6-sulfonylaminoindanyl

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19 6155
Scheme 1a
a Reagents and conditions: (i) Ar(Het)SO2Cl, pyridine, rt; (ii) Fe, AcOH-H2O, 90 °C; (iii) (a) K2CO3, dry DMF, rt, (b) MeI, rt.
Scheme 2a
a Reagents and conditions: (i) aminoguanidine hydrogencarbonate or 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide, 37% HCl, solvent, reflux.
34 (Ki=1.2 ( 0.6 nM), 5-sulfonylaminoindanyl 36 (Ki=2.6 (
0.5 nM), and 4-sulfonylaminoindanyl 37 (inhibition of 2% at
100 nM) permitted us to rule out additional studies with
compounds containing a sulfonamide moiety at the indane
4-position. Additional studies with compounds bearing a
3,3-dimethylindane core, such as 38 (Ki=5.2 ( 0.4 nM), or a
N-methyl sulfonamide group, such as 39 (Ki = 4.1 ( 0.2 nM),
showed ∼ 3-fold weaker affinities compared to compound 34.
Yet when the guanylhydrazone pattern was changed by an
imidazolinylhydrazone group, compound 40 (Ki = 2.2 (
0.3 nM) gave a similar affinity to 34 (Figure S2, SI). Interest-
ingly, the indanylsulfonamides 34-36 and 40 displayed a similar
high 5-HT6 affinity to the 1-type indenysulfonamides, e.g. 3
(Ki=4.5 ( 1.9 nM),12 and to the 9-type indolylsulfonamide,
e.g. 11 and 12 (Ki=1.0 nM).24
To establish the correlation between receptor affinity and
functional activity, efficacy of these ligands was determined in
a cAMP homogeneous time-resolved fluorescence (HTRF)
assay format in HEK-293F cells stably expressing the hu-
man 5-HT6 receptor.29-31Guanylhydrazones 31-41 inhibited

6156 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19
Mesquida et al.
Table 1. Physical Data, 5-HT6 Receptor Affinity, and Functionality of Compounds 5 and 31-41
compd
R1
R2, R3
Ar/Het
precursor
yield (%)a
mp (°C)a
Ki (nM)b,c
Imax (%)b,d
IC50 (nM)b,d
5e
Het1
Ar1
3 ( 0.3
62 ( 29
26 ( 8
70 ( 12
1.2 ( 0.6
1.6 ( 0.1
2.6 ( 0.5
nd
100 ( 3
127 ( 9
187 ( 37
ndI
1580 ( 40
53 ( 9
581 ( 16
nd
31
32
33
34
35f
36
37g
38
39
40
41h
18
19
19
21
22
24
26
29
30
21
29
36
63
70
59
95
30
66
93
49
41
69
256-257
190-191
264-265
219-220
>300
Ar2
Ar2
Het1
Het1
Het1
Het1
Het1
Het1
Het1
Het1
127 ( 9
157 ( 6
173 ( 25
nd
96 ( 25
58 ( 9
47 ( 5
nd
Me
249-250
>300
Me
Me
225-226
253-254
245-246
>300
5.2 ( 0.4
4.1 ( 0.2
2.2 ( 0.3
nd
146 ( 12
102 ( 9
173 ( 45
nd
238 ( 32
54 ( 7
176 ( 69
nd
a Compounds 31, 32, 34-39 were prepared as hydrochloride salts, and compounds 33, 40 and 41 could be a mixture of hydrohalide salts. b Data are
the mean ( SEM of three experiments. c Ki was calculated when inhibition at 100 nM > 80%. d Antagonism was expressed as Imax and IC50 values. e See
ref 13. f Racemic mixture. g Inhibition of 2% at 100 nM. h Inhibition of 77% at 100 nM. I nd, not determined.
5-HT stimulated cAMP production with IC50 values g47 nM
and Imax values in the range of 102-173%. It was also
interesting to observe that compounds 31-41 were more
potent antagonists than the conformationally rigid 2-type
reported in the SI. We describe herein the general procedure for
the preparation of the final products. For targeted compounds,
satisfactory high-resolution mass spectra and HPLC analyses
were obtained, confirming >95% purity.
Synthesis of Indanylsulfonamide Guanylhydrazones 31-41.
General Procedure. To a solution of indanone sulfonamides
18, 19, 21, 22, 24, 26, 29, and 30 (1.0 equiv) in the suitable solvent
was added a suspension of aminoguanidine hydrogencarbonate
or 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide (1.1
equiv) in an excess of hydrochloric acid, and the mixture was
heated to reflux for 18 h. The reaction mixture was cooled in an
ice bath to obtain a solid that was isolated by filtration or the
crude reaction was evaporated to dryness and was purified by
crushing with a suitable solvent.
5-HT6 Binding Assay. Affinity of compounds at 5-HT6
receptors was evaluated utilizing membranes from HEK-293 cells
with human 5-HT6 serotonin receptor expressed and tritiated
lysergic acid diethylamide ([3H]-LSD) as the radioligand28
(see SI).
indenylsulfonamides, e.g. 5 with Imax=100 ( 3% and IC50
=
1.6 ( 0.4 μM (Table 1). The binding affinities of 31, 32, and
34-40 for a panel of several serotonin and adrenergic receptors
as well as the serotonin transporter (SERT) were negligible
(Table S1, SI).
Conclusions
In our continued search for 5-HT6 serotonin receptor
ligands related to the disubstituted N-[3-(aminoethyl)inden-
5-yl]sulfonamide agonists 1, the present study was designed to
examine a structural change of the basic amine moiety at the
indene 3-position. The replacement of the conformationally
flexible N,N-(dimethylamino)ethyl side chain by a rigid guanyl-
hydrazone moiety led to the identification of novel indanylsul-
fonamide guanylhydrazones 6 with excellent binding affinities
at the 5-HT6 receptor (Ki g1.2 nM). In a functional adenylyl
cyclase assay, 6-type ligands behaved as full 5-HT6 receptor
antagonists showing values of IC50 g 47 nM and Imax e 173%,
with negligible activities against several serotoninergic and
adrenergic receptors as well as the SERT. Among them,
compounds 34 and 35 displayed the finest biological profile.
Adenylyl Cyclase Activity Assay. Functional effects of the
compounds were evaluated by cAMP measurements on HEK-
293F cells stably expressing the human 5-HT6 receptor using a
HTRF assay format (see SI).29-31
Acknowledgment. This research was supported by ESTEVE,
Barcelona, Spain, through projects FBG2004/05-302663 and
ꢀ
FBG2006/07-303647 Fundacio Bosch i Gimpera-Universitat
de Barcelona, Spain. S.L.-P. thanks ESTEVE for a graduate
fellowship (2004-07) and the AGAUR for a predoctoral 2008-
F.I. fellowship. Thanks are also due to the AGAUR, Grup de
Recerca Consolidat 2005SGR158 and 2009SGR562.
Experimental Section
Chemistry. General methods, materials, full experimental
details, and structural characterization of all compounds are

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19 6157
Supporting Information Available: Full experimental condi-
tions and spectral data for all products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
guanylhydrazones. Synthesis and evaluation as Inotropic Agents.
Biorg. Med. Chem. Lett. 1998, 8, 3217–3222.
(19) Bryant, H. U.; Nelson, D. L.; Button, D.; Cole, H. W.; Baez, M. B.;
Lucaites, L.; Wainscott, D. B.; Whitesitt, C.; Reel, J.; Simon, R.;
Koppel, G. A. A novel class of 5-HT4 receptor antagonists: aryl
aminoguanidines. Life Sci. 1996, 59, 1259–1268.
References
(20) (a) Khownium, K.; Wood, S. J.; Miller, K. A.; Balakrishna, R.;
Nguyen, T. B.; Kimbrell, M. R.; Georg, G. I.; David, S. A. Novel
endotoxin-sequestering compounds with terephthalaldehyde-bis-
guanylhydrazone scaffolds. Biorg. Med. Chem. Lett. 2006, 16,
1305–1308. (b) Wei, R. G.; Arnaiz, D. O.; Chou, Y.-L.; Davey, D.;
Dunning, L.; Lee, W.; Lu, S.-F.; Onuffer, J.; Ye, B.; Phillips, G. CCR5
receptor antagonists: Discovery and SAR study of guanylhydrazone
derivatives. Biorg. Med. Chem. Lett. 2007, 17, 231–234.
(21) Buchheit, K.-H.; Gamse, R.; Giger, R.; Hoyer, D.; Klein, F.;
Kloppner, E.; Pfannkuche, H.-J.; Mattes, H. The Serotonin
5-HT4 Receptor. 1. Design of a New Class of Agonists and
Receptor Map of the Agonist Recognition Site. J. Med. Chem.
1995, 38, 2326-2330 and references cited.
(22) Buchheit, K.-H.; Gamse, R.; Giger, R.; Hoyer, D.; Klein, F.;
Kloppner, E.; Pfannkuche, H.-J.; Mattes, H. The Serotonin
5-HT4 Receptor. 2. Structure-Activity Studies of the Indole
Carbazimidamide Class of Agonists. J. Med. Chem. 1995, 38,
2331–2338.
(23) Cole, D. C.; Stock, J. R.; Lennox, W. J.; Bernotas, R. C.; Ellingboe,
J. W.; Boikess, S.; Coupet, J.; Smith, D. L.; Leung, L.; Zhang,
G.-M.; Feng, X.; Kelly, M. F.; Galante, R.; Huang, P.; Dawson, L.
A.; Marquis, K.; Rosenzweig-Lipson, S.; Beyer, C. E.; Schechter,
L. E. Discovery of N1-(6-Chloroimidazo[2,1-b][1,3]-thiazole-5-sul-
fonyl)tryptamine as a potent, selective, and orally active 5-HT6
receptor agonist. J. Med. Chem., 2007, 50, 5535-5538.
(1) Monsma, F. J., Jr.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley,
D. R. Cloning and expression of a novel serotonin receptor with
high affinity for tricyclic psychotropic drugs. Mol. Pharmacol.
1993, 43, 320-327 and references cited.
(2) Ruat, M.; Traiffort, E.; Arrang, J. M.; Tardivel-Lacombe, J.; Diaz,
J.; Leurs, R.; Schwartz, J. C. A novel rat serotonin (5-HT6)
receptor: molecular cloning, localization and stimulation of cAMP
accumulation. Biochem. Biophys. Res. Commun. 1993, 193, 268–
276.
(3) Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.;
Lachowicz, J. E.; Meltzer, H. Y.; Sibley, D. R.; Roth, B. L.;
Hamblin, M. W. Cloning, characterization, and chromosomal
localization of a human 5-HT6 serotonin receptor. J. Neurochem.
1996, 66, 47–56.
(4) Sebben, M.; Ansanay, H.; Bockaert, J.; Dumuis, A. 5-HT6 recep-
tors positively coupled to adenylyl cyclase in striatal neurones in
culture. NeuroReport 1994, 5, 2553–2557.
(5) Sleight, A. J.; Boess, F. G.; Bos, M.; Bourson, A. The putative
5-HT6 receptor: localization and function. Ann. N. Y. Acad. Sci.
1998, 861, 91–96.
(6) Glennon, R. A. Higher-End serotonin receptors: 5-HT5, 5-HT6,
and 5-HT7. J. Med. Chem. 2003, 46, 2795–2812.
(7) Nichols, D. E.; Nichols, C. D. Serotonin Receptors. Chem. Rev.
2008, 108, 1614–1641.
(8) Johnson, C. N.; Ahmed, M.; Miller, Neil, D. 5-HT6 receptor
antagonists: prospects for the treatment of cognitive disorders
including dementia. Curr. Opin. Drug Discovery Dev. 2008, 11,
642–654.
(9) Heal, D. J.; Smith, S. L.; Fisas, A.; Codony, X.; Buschmann, H.
Selective 5-HT6 receptor ligands: progress in the development of a
novel pharmacological approach to the treatment of obesity and
related metabolic disorders. Pharmacol. Ther. 2008, 117, 207–231.
(10) Liu, K. G.; Robichaud, A. J. 5-HT6 Antagonists as potential
treatment for cognitive dysfunction. Drug Dev. Res. 2009, 70,
145–168.
(24) (a) Cole, D. C.; Kelly, M. G.; Bravo, B. A.; Palmer, Y. L. (1-Sub-
stituted-indol-3-yl)alkylidenehydrazinecarboximidamide deriva-
tives as 5-hydroxytryptamine-6 ligands. US Patent US 2003/
0232843 A1, CAN 140:27762, 2003. (b) Cole, D. C.; Kelly, M. G.;
Nunn, D. S.; Greenblatt, L. P. Indolylalkylidenehydrazinecarboximida-
mide derivatives as 5-hydroxytryptamine-6 ligands. US Patent US
2004/0002527 A1, CAN 140:77025, 2004.
ꢁ
(25) (a) Merce, R.; Andaluz, B.; Frigola, J. Sulphonamide derivatives,
their preparation thereof and the application of same as medica-
ments. World Patent WO 03/042175 A1, CAN 138:401602, 2003.
ꢁ
(b) Holenz, J.; Merce, R.; Díaz, J. L.; Guitart, X.; Codony, X.; Dordal,
ꢀ
ꢀ
ꢁ
(11) Alcalde, E.; Mesquida, N.; Frigola, J.; Lopez-Perez, S.; Merce, R.
Indene-based scaffolds. Design and synthesis of novel serotonin
5-HT6 receptor ligands. Org. Biomol. Chem. 2008, 6, 3795–3810.
ꢀ
A.; Romero, G.; Torrens, A.; Mas, J.; Andaluz, B.; Hernandez, S.;
ꢀ
ꢀ
ꢀ
Monroy, X.; Sanchez, E.; Hernandez, E.; Perez, R.; Cubí, R.; Sanfeliu,
O.; Buschmann, H. Medicinal chemistry driven approaches toward
novel and selective serotonin 5-HT6 receptor ligands. J. Med. Chem.
2005, 48, 1781–1795.
ꢀ
ꢀ
ꢁ
(12) Alcalde, E.; Mesquida, N.; Lopez-Perez, S.; Frigola, J.; Merce, R.
An Indole-Indene Switch: Discovery of Novel Indenylsulfona-
mides as 5-HT6 Serotonin Receptor Agonists. J. Med. Chem. 2009,
52, 675–687.
(26) Schechter, L. E.; Lin, Q.;Smith, D. L.; Zhang, G.;Shan, Q.; Platt, B.;
Brandt, M. R.; Dawson, L. A.; Cole, D.; Bernotas, R.; Robichaud,
A.; Rosenzweig-Lipson, S.; Beyer, C. E. Neuropharmacological
profile of novel and selective 5-HT6 receptor agonists: WAY-
181187 and WAY-208466. Neuropsychopharmacology 2007, 1–13.
ꢁ
(13) Frigola, J.; Merce, R.; Holenz, J.; Alcalde, E.; Mesquida, N.;
ꢀ
ꢀ
Lopez-Perez, S. Preparation of indene derivatives for treatment
of 5-HT6 receptors mediated diseases. World Patent WO 07/
054257 A2, CAN 146:521555, 2007.
ꢀ
ꢀ
ꢁ
(27) Alcalde, E.; Mesquida, N.; Lopez-Perez, S.; Frigola, J.; Merce, R.;
Holenz, J.; Substituted indanyl sulfonamide compounds, their
preparation ans use as medicaments. World Patent WO 08/
015137 A2, CAN 148:191738, 2008.
(14) Andreani, A.; Rambaldi, M.; Locatelli, A.; Bossa, R.; Fraccari, A.;
Galatulast, I. Potential Antitumor Agents. 21. Structure Determination
and Antitumor Activity of Imidazo[2,1-b]thiazole Guanylhydrazones.
J. Med. Chem. 1992, 35, 4634–4637.
(28) (a) Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.;
Monsma, F. J., Jr.; Shen, Y.; Meltzer, H. Y.; Sibley, D. R. Binding
of typical and atypical antipsychotic agents to 5-hydroxytrypta-
mine-6 and 5-hydroxytryptamine-7 receptors. J. Pharmacol. Exp.
Ther. 1994, 268, 1403–1410. (b) Munson, P. J.; Rodbard, D. LIGAND:
A versatile, computerized approach for characterization of ligand-
binding systems. Anal. Biochem. 1980, 107, 220–239.
(15) (a) Andreani, A.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi,
M.; Recanatini, M.; Garaliene, V. Potential Antitumor Agents.
Part 29: Synthesis and Potential Coanthracyclinic Activity of
Imidazo[2,1-b]thiazole Guanylhydrazones. Biorg. Med. Chem.
2000, 8, 2359-2366 and references cited. (b) Andreani, A.; Burnelli,
S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.;
Varoli, L.; Calonghi, N.; Cappadone, C.; Farruggia, G.; Zini, M.;
Stefanelli, C.; Masotti, L.; Radin, N. S.; Shoemaker, R. H. New
Antitumor Imidazo[2,1-b]thiazole Guanylhydrazones and Analogues.
J. Med. Chem. 2008, 51, 809-816 and references cited.
(16) Papanastasiou, I.; Tsotinis, A.; Kolocouris, N.; Prathalingam, S.
R.; Kelly, J. M. Design, Synthesis, and Trypanocidal Activity of
New Aminoadamantane Derivatives. J. Med. Chem. 2008, 51,
1496–1500.
(17) Stanek, J.; Caravatti, G.; Frei, J.; Furet, P.; Mett, H.; Schneider, P.;
Regenass, U. 4-Amidinoindan-l-one 20-Amidinohydrazone: A
New Potent and Selective Inhibitor of S-Adenosylmethionine
Decarboxylase. J. Med. Chem. 1993, 36, 2168–2171.
ꢁ
(29) Fisas, A.; Codony, X.; Romero, G.; Dordal, A.; Giraldo, J.; Merce,
R.; Holenz, J.; Heal, D.; Buschmann, H.; Pauwels, P. J. Chronic
5-HT6 receptor modulation by E-6837 induces hypophagia and
sustained weight loss in diet-induced obese rats. Br. J. Pharmacol.
2006, 148, 973–983.
ꢀ
ꢀ
(30) Romero, G.; Sanchez, E.; Pujol, M.; Perez, P.; Codony, X.; Holenz,
J.; Buschmann, H.; Pauwels, P. J. Efficacy of selective 5-HT6
receptorligandsdeterminedby monitoring5-HT6 receptor-mediated
cAMP signaling pathways. Br. J. Pharmacol. 2006, 148, 1133–
1143.
ꢀ
(31) Romero, G.; Pujol, M.; Perez, P.; Buschmann, H.; Pauwels, P. J.
Whole spectrum analysis of ligand efficacy at constitutively active
human wild-type and S267K 5-HT6 receptors in HEK-293F cells.
J. Pharmacol. Toxicol. Methods 2007, 55, 144–150.
ꢀ
(18) Melero, C. P.; Sevillano, L. G.; Caballero, E.; Tome, F.; Carron,
R.; Montero, M. J.; San Feliciano, A.; Medarde, M. Hydroindenic-
ꢀ