Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT1 melatoninergic ligands

Article abstract of DOI:10.1016/j.bmc.2010.04.008

Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these liga

Full text of DOI:10.1016/j.bmc.2010.04.008

Bioorganic & Medicinal Chemistry 18 (2010) 3426–3436
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and pharmacological evaluation of novel naphthalenic
derivatives as selective MT1 melatoninergic ligands
Christophe Mésangeau a,b, Basile Pérès a,b, Carole Descamps-François a,b, Philippe Chavatte a,b
,
Valérie Audinot d, Sophie Coumailleau d, Jean A. Boutin d, Philippe Delagrange c, Caroline Bennejean d,
Pierre Renard c, Daniel H. Caignard c, Pascal Berthelot a,b, Saïd Yous a,b,
*
a Univ Lille Nord de France, F-59000 Lille, France
b UDSL, EA GRIIOT, UFR Pharmacie, F-59000 Lille, France
c Département des Sciences Expérimentales, Institut de Recherches Servier, 92150 Suresnes, France
d Institut de Recherches Servier, 78290 Croissy-sur-Seine, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units
are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions
at melatonin receptors. Several of these ligands are MT1-selective with nanomolar or subnanomolar affin-
ity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes,
N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide
(36), a subnanomolar MT1 ligand with an 11-fold preference over MT2 receptors, is a full antagonist on both
receptors. Our results also confirm that the selectivity seen for the MT1 receptor arises predominantly from
steric factors and is not a consequence of the bridging of melatonin receptor dimers.
Received 12 January 2010
Revised 31 March 2010
Accepted 1 April 2010
Available online 7 April 2010
Keywords:
Melatonin
MT1
Antagonist
Selective ligands
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, several selective MT215–27 and MT3,28 receptor ligands
have been described as competitive agonists or antagonists with
Melatonin (N-acetyl-5-methoxytryptamine, MLTa, Chart 1)1 is a
neurohormone synthesized and secreted by the pineal gland fol-
lowing a circadian rhythm, with peak levels occurring at night. This
hormone plays a role in a myriad of physiological functions includ-
ing, in mammals, the control of seasonal reproduction,2 circadian
adjustments,3 immunoresponsiveness,4 vascular regulation,5 and
cancer growth inhibition.6 Nevertheless, clinical trials have only
confirmed the resynchronizing effects of melatonin, which might
be of interest in the regulation of disrupted circadian rhythms
and sleep disorders. The diversity of melatonin response within
the body may be attributed to the fact that its receptors are ex-
pressed in the central nervous system and in a wide variety of
peripheral tissues.7–11
varying degrees of selectivity. Several antagonists such as luzin-
dole,29 the first MT2 receptor competitive antagonist discovered,
and 4P-PDOT (4-phenyl-2-propionamidotetralin),30 allowed for
the identification of several physiological responses mediated by
MLT receptors. The former demonstrated the role of MT2 receptors
in mediating inhibition of dopamine release in rabbit retina, while
both compounds blocked melatonin-mediated phase advances of
circadian rhythms in mice.3
However, elucidation of the pathophysiological function of the
MT1 receptor has been hampered mainly by the limited availability
of selective full agonist and/or full antagonist for this receptor
subtype. Consequently, synthesis and design of selective MT1
receptor ligands with better affinity and selectivity may aid in
the assessment and characterization of the role of this receptor.
A few examples of selective MT1 receptor ligands have been
reported in the literature. One of the first selective MT1 ligand
described, 2 (S24268, Chart 1)31 consists of two N-(2-(naphtha-
len-1-yl)ethyl)acetamide moieties, or desmethoxy agomelatine,
dimerized at the 6-position of the aromatic ring (MT2/MT1 = 70).
Constitutive homo (MT1–MT1 or MT2–MT2) and hetero-dimeriza-
tion (MT2–MT1) among high affinity melatonin receptors were
observed in Human Embryonic Kidney (HEK 293) cells and it was
In mammals, MLT activates two high affinity G-protein-coupled
cell-membrane receptors, MT1 and MT2, which were cloned in the
mid-1990s.2,3,7,8 Moreover, another MLT binding site with a lower
affinity profile, denoted MT3,12 has been characterized as a melato-
nin-sensitive form of the human enzyme quinone reductase 2.13,14
* Corresponding author. Tel.: +33 3 2096 4375.
E-mail address: said.yous@univ-lille2.fr (S. Yous).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.04.008

C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
3427
NHCOCH3
NHCOCH3
CH3
O
CH3
O
N
H
Melatonin (MLT)
1, Agomelatine
NHCOCH3
NHCOCH3
NHCOCH3
O
( )nO
NHCOCH3
2, (S24268)
3, n= 3 ; 4, n = 4
NHCOCH3
NHCOCH3
N
N
O
O
( )n
O
N
NHCOc-C3H7
N
N
( )4
CH3
CH3
5, Azaindole Dimers
6, Benzoxazole derivative
NHCOCH3
NHCOCH3
CH3
O
CH3
O
CO2 (CH2)n O2C
N
N
H
H
7, Melatonin Dimers
Chart 1. Chemical structures of melatonin, agomelatine and several representative MT1-selective ligands.
demonstrated that MT1 homodimers and MT2–MT1 heterodimers
represent the majority of all complexes.32,33
cannot test this directly with current technology. However multi-
ple sites exist within a single receptor which can still lead to selec-
tivity allowing the use of dimer drugs. The molecular architecture
of ligands and receptor mutation experiments reveal a three bind-
ing site hypothesis for the interaction of ligands with monoamine
G-protein coupled receptors: implications for combinatorial ligand
design.36
A series of dimers in which two azaindole pharmacophores (5,
Chart 1)37 were connected together through a linear alkyl chain,
was later reported, but these compounds displayed lower affinity
and weaker selectivity (2–20-fold) compared to our first series of
dimers. Recently, novel benzoxazole derivatives (6, Chart 1)38 has
been reported as a highly potent human MT1 ligand with moderate
receptor selectivity (selectivity (S) = 35). New melatonin dimeric
derivatives (7, Chart 1)39 with two melatonin units linked together
with a polymethylene spacer through the MLT acetamide function
or through a C-2 carboxyalkyl group were also described. However,
they did not show significant MT1 selectivity. In this study, we
present a novel series of MT1-selective compounds based on our
previous work on agomelatine dimers.
In light of the structural framework of these receptors, a series
of agomelatine dimers (3, 4, Chart 1)34 was synthesized in our lab-
oratory in accordance with the ‘bivalent ligand’ approach em-
ployed by Portoghese. The premise of this concept was that a
bivalent ligand with an optimal distance between the two pharma-
cophores would exhibit a greater potency than that derived from
the sum of its monovalent counterparts by allowing the bridging
between dimeric receptors.35 Investigation of varying lengths of
the alkyl linker determined an optimal distance of 3–4 carbons be-
tween the agomelatine moieties (Chart 1, MT2/MT1 = 224 for com-
pound 3 and MT2/MT1 = 120 for compound 4). Since a spacer of 3–4
carbons did not attain the length required to permit a bivalent li-
gand to bridge neighboring receptors, it was suggested that the
second pharmacophore participated in steric interactions in or
near the MT1 receptor pocket but not in or near the MT2 receptor
pocket.
An alternative possibility is that the receptors dimerise and the
two recognition sites are brought close together. However, we

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C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
Compound 4 a symmetric dimer bearing a four carbons alkyl
Reaction of compound 8b with an excess of 1,4-dibromobutane
in the presence of potassium carbonate in acetonitrile provided the
bromobutyl analogue 14 (Scheme 2). Phenolic derivatives 9b–11b
and 13 were then alkylated with the bromobutyl derivative 14 in
the presence of potassium carbonate in acetonitrile to give the cor-
responding O-alkylated derivatives 15–17 and 19 (Scheme 2).
Deprotection of 17–18 was carried out with magnesium and
ammonium chloride in methanol.28
Heterodimers 24–26 and homodimers 29–30 were prepared
according to the synthetic pathway illustrated in Scheme 3. The
first step involved the reaction of (7-hydroxynaphthalen-1-yl)eth-
ylamine (20) with di-tert-butyldicarbonate in methylene chloride
to generate the carbamate 21. This compound was then alkylated
with 14 or 1,4-dibromobutane to give compounds 22 and 27,
respectively. Removal of the Boc protecting group of these com-
pounds was carried out with a saturated methanolic solution of
spacer, was chosen as a template and modified by altering one of
its agomelatine moieties, generating a series of novel asymmetric
heterodimers.
2. Chemistry
Key intermediates in the synthesis of the target compounds 15,
16, 18 and 19 (Table 1) are the corresponding hydroxy derivatives
8b–11b and 13 (Scheme 1). Derivatives 8b–11b were obtained from
the previously described methoxy derivatives 8a–11a by cleavage
of the methyl ether using boron tribromide (Scheme 1).40–44 The
reaction of melatonin with benzenesulfonyl chloride in the pres-
ence of sodium hydroxide and a phase transfer catalyst provided
the corresponding sulfonamide 12.28 Subsequent treatment of 12
with boron tribromide afforded the hydroxy compound 13.
Table 1
MT1 and MT2 receptor binding affinities of compounds 15–19
NHCOCH3
NHCOCH3
NHCOCH3
NHCOCH3
O
O
O
O
( )4
( )4
X
4, 15-17
19
Compd
X
Ki (nM) MT1
Ki (nM) MT2
S (MT2/MT1)
4
15
16
18
19
CH@CH
O
S
NH
—
0.60 0.04
1.38 0.52
3.47 1.13
4.04 0.90
0.26 0.01
72.70 22.20
13.90 1.85
16.90 1.90
84.30 18.80
6.79 1.73
120
10
5
21
26
NHCOCH3
NHCOCH3
CH3
O
HO
(a)
X
X
8a X = CH=CH
9a X = O
10a X = S
8b X = CH=CH
9b X = O
10b X = S
NHCOCH3
NHCOCH3
CH3
O
HO
(a)
11b
11a
NHCOCH3
NHCOCH3
NHCOCH3
CH3
O
CH3
O
(b)
(a)
HO
N
N
N
H
SO2C6H5
SO2C6H5
MLT
12
13
Scheme 1. Preparation of phenolic compounds: 8b–11b and 13. Reagents: (a) BBr3, CH2Cl2; (b) NaOH, (n-Bu)4NþNHSO4ꢀ, C6H5SO2Cl.

C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
3429
NHCOCH3
NHCOCH3
NHCOCH3
NHCOCH3
O
Br
OH
(c)
O
O
(a)
( )4
( )4
X
8b
14
15 X = O
16 X = S
(b)
17 X = NSO2C6H5
18 X = NH
NHCOCH3
NHCOCH3
(d)
O
O
( )4
19
Scheme 2. Synthesis of compounds 15, 16, 18 and 19. Reagents: (a) Br(CH2)4Br, K2CO3, CH3CN,
D
; (b) 11b, K2CO3, CH3CN,
D
; (c) 9b or 10b or 13, K2CO3, CH3CN,
D
; (d) Mg,
NH4Cl, MeOH.
NH2,HCl
NHBoc
NHBoc
NHCOCH3
OH
OH
O
( )4O
(b)
(a)
20
22
21
(c)
(d)
NHBoc
NHBoc
NH2,HCl
NHCOCH3
O
O
( )4
O
O
( )4
27
23
(e)
(d)
NHCOR1
NHCOR2
NHCOR2
NHCOCH3
O ( )4
O
O
O
( )4
R1=R2= NH2, HCl, 28
R2 = cyclopropyl, 24
R2 = furyl, 25
(e)
R1 = R2 = cyclopropyl, 29
R1 = R2 = allyl, 30
R2 = allyl, 26
Scheme 3. Synthesis of compounds 24–26, 29 and 30. Reagents: (a) Et3N, (Boc)2O, CH2Cl2; (b) 14, K2CO3, CH3CN, reflux; (c) Br(CH2)4Br, K2CO3, CH3CN, reflux; (d) HCl(g),
MeOH; (e) RCOCl, K2CO3, H2O, CHCl3 for 24, 25 and 29 or CH2CHCH2COOH, EDCI, CH2Cl2 for 26 and 30.
hydrochloric acid. The N-acylated compounds 24–26 and 29, 30
were then prepared from amines 23 and 28 by reaction with the
appropriate acyl chloride in the presence of potassium carbonate
or by reaction with vinylacetic acid in the presence of EDCI.
Preparation of compounds 35–38 is reported in Scheme 4. Com-
pounds 31b and 32b were easily obtained from the commercially
available 31a and 32a by action of concentrated hydrobromic acid
in refluxing acetic acid. These acids were then esterified using thio-
nyl chloride in methanol to give compounds 33 and 34, which were
then reacted with 14 to form the respective dimers 35 and 36.
Finally, treatment of 35 and 36 with sodium hydroxide led to the
heterodimers 37 and 38.
Compounds 41–43 were prepared as shown in Scheme 5. 4-(40-
Hydroxyphenyl)benzoic acid was converted to the corresponding
ester 39 using thionyl chloride in methanol. Alkylation of 39 with
the bromobutyl derivative 14 gave dimer 41, which was treated
with sodium hydroxide to give the target acid 42. Reduction of
the ester group of 39 with lithium aluminium hydride gave the
hydroxymethyl derivative 40, which was then alkylated with com-
pound 14 to give the target compound 43.

3430
C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
CH3
O
8
8
HO
COOH
X
(a)
COOCH3
X
31b X = H (8)
32b X = CH3 (6)
6
6
(b)
33 X = H (8)
34 X = CH3 (6)
31a X = H (8)
32a X = CH3 (6)
(c)
NHCOCH3
8
O
O
COOCH3
( )4
35 X = H (8)
36 X = CH3 (6)
6
X
(d)
NHCOCH3
8
O
O
COOH
X
37 X = H (8)
38 X = CH3 (6)
( )4
6
Scheme 4. Synthesis of compounds 35–38. Reagents: (a) HBr 47% in water, AcOH,
D
; (b) SOCl2, MeOH; (c) 14, K2CO3, CH3CN, reflux; (d) NaOH, H2O, MeOH, THF.
HO
HO
HO
(d)
(a)
OH
CO2CH3
COOH
39
40
(b)
(b)
NHCOCH3
NHCOCH3
O
O
O
O
( )4
( )4
43
OH
COOR
R= CH3, 41
R= H, 42
(c)
Scheme 5. Synthesis of compounds 41–43. Reagents: (a) SOCl2, MeOH; (b) 14, K2CO3, CH3CN, reflux; (c) NaOH, H2O, MeOH, THF; (d) LiAlH4, THF.
3. Pharmacology
Table 2
Modulation of the N-acyl side chain
All final compounds were tested in binding studies for effi-
ciency in human MT1 and MT2 receptors transfected in Chinese
Hamster Ovarian (CHOa) cells, using 2-[125I]-iodomelatonin as
NHCOR1
NHCOR2
radioligand.31 The [35S]-GTP
cS binding assay using CHO cell lines
stably expressing the human MT1 or MT2 receptors was used to
determine the functional activity of the compounds.
O
O
( )4
4. Results and discussion
Compd R1
R2
Ki (nM)
MT1
Ki (nM) MT2
S
The chemical structures, binding affinities and MT2/MT1 selec-
tivity ratios of the new compounds are presented in Tables 1–4.
The results of the evaluation of the intrinsic activity are shown in
Table 5.
The synthesis and binding properties at MT1 and MT2 receptors
of the first series of agomelatine dimers, in which two agomelatine
moieties are linked together through their methoxy substituent by
a polymethylene side chain, has been reported earlier by our
(MT2/
MT1)
4
24
25
26
29
30
CH3
CH3
CH3
CH3
CH3
c-C3H5
2-Furyl
CH2CH@CH2 0.79 0.22
c-C3H5 1.01 0.23
0.60 0.04 72.70 22.20 120
1.07 0.34 11.10 2.73
0.64 0.00 11.80 2.81
10
18
11
13
12
8.45 1.66
13.6 0.85
10.9 1.05
c-C3H5
CH2CH@CH2 CH2CH@CH2 0.92 0.26

C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
3431
Table 3
select compound (4) as a lead compound to investigate struc-
ture-affinity and structure–activity relationships for MT1 and MT2
receptors.
Replacement of the N-acyl side chain by an ester or an acid group
NHCOCH3
Numerous reasons exist for the use of bioisosterism in medici-
nal chemistry. This includes the necessity to gain selectivity for a
determined receptor, modify the intrinsic activity and optimize
pharmacokinetics. Bioisosteric replacement of one of the agomela-
tine unit of our lead compound with benzofuran, benzothiophene,
and indole nuclei led to compounds 15, 16 and 18, which displayed
higher affinities for the MT1 receptors than for the MT2 receptors
(Table 1). However, their selectivities (MT2/MT1 = 10, 5, 21, respec-
tively) remained inferior to that of the reference ligand (4; MT2/
MT1 = 120). Interestingly, tetralinic analogue 19 displayed greater
affinity for the MT1 receptor (0.26 nM) than compound (4) and a
selectivity ratio of 26.
8
O
O
( )4
R3
6
Compd
R3
Ki (nM) MT1
Ki (nM) MT2
S (MT2/MT1)
35
36
37
38
8-CH2CO2CH3
6-CH(CH3)CO2CH3
8-CH2CO2H
0.07 0.01
0.37 0.08
9.10 1.11
1.51 0.42
1.84 0.16
4.22 1.76
45.80 6.65
59.10 1.70
26
11
5
6-CH(CH3)CO2H
39
The influence of the N-acylamino group of the lead compound
was also examined with compounds 24–26, 29 and 30 (Table 2)
as it has been reported that this group plays a primary role in ago-
nist action to MLT receptors.41 To this end, one or both of the
methyl groups of the N-acylamido side chains were replaced by
cyclopropyl, furyl and allyl moieties. While affinity was retained
for MT1, increased affinity for MT2 was also seen, which resulted
in a loss of selectivity, the MT2/MT1 ratios between 10 and 18.
The N-acyl side chain has a primary importance for the efficacy
of binding of a ligand to melatonin receptors. Removal of this fea-
ture usually results in a complete loss of affinity and is equivalent
to converting a melatoninergic ligand to a non-melatoninergic li-
gand. A small set of analogues was synthesized with a view to
probing the importance of having an N-acyl side chain on both
units of the dimer. Replacement of one ethylacetamide group by
either methyl acetate or acetic acid in position 8 and by methyl
2-propanoate or its corresponding acid in position 6 had no favor-
able effect on the selectivity (Table 3, compounds 35–38). In this
series, compound 35 presented an excellent affinity for the MT1
receptor (0.07 nM) and an affinity of 1.84 nM for the MT2 receptor,
giving a selectivity ratio of 26. Conversion of the ester to its corre-
sponding acid resulted in a reduced affinity for both MT1 and MT2
(130-fold and 25-fold, respectively). Compound 36, bearing a
methyl 2-propanoate function in position 6, showed a subnanom-
olar MT1 affinity (0.37 nM) and an 11-fold selectivity over MT2.
Its hydrolysis led to reduced affinity for MT1 and MT2 (4-fold and
Table 4
Replacement of an agomelatine molecule by a biphenyl group
NHCOCH3
O
O
( )4
R4
Compd
R4
Ki (nM) MT1
Ki (nM) MT2
S (MT2/MT1)
41
42
43
CO2CH3
CO2H
CH2OH
2.37 0.89
0.55 0.01
0.09 0.00
19.10 1.57
51.30 3.12
6.53 0.07
8
93
72
group.34 The most selective compounds contained three and four
carbon spacers. The homodimer with a linker length of four car-
bons (4, MT2/MT1 = 120) was later predicted in silico to have a bet-
ter metabolic stability than its more selective three carbon spacer
homolog. In the study presented herein, we therefore decided to
Table 5
Intrinsic activity values
Compd
MT1
MT2
KB (nM)
Imax (%)
EC50 (nM)
Emax (%)
KB (nM)
Imax (%)
EC50 (nM)
Emax (%)
MLT33
133
4
nd
nd
nd
nd
2.2 0.4
1.6 0.4
110
101
25
2
6
1
nd
nd
nd
nd
80
0.49 0.04
0.10 0.04
405 35
104
91
39
6
7
3
11 1.0
27.5 5.9
5.43 2.3
10.6 6.0
6.24
5.2 1.1
7.5
4.3 0.89
5.7 0.17
8.13
68 10
42.5 11.5
46 14
48.5 4.5
68.5 3.5
75 5.1
72.3 1.4
71 3.6
77.3 2.84
63 3.2
30
61 18
nd
34
nd
73
7
29 11
160 55.5
60.8 25
300 143
122 36
31.1 9.9
25 11.1
19 3.75
6.7 2.8
11.3 0.6
9.05 1.5
643 211
20.5 7.4
26 0.8
>1 ꢁ 10ꢀ5
nd
4
15
16
18
19
24
25
26
29
30
35
36
37
38
41
42
43
2.49 0.49
1.94 0.62
2.38 1.02
7.75 71.9
9.1 4.3
78.5 18.5
55.5 0.5
79 22.7
32.7 9.9
27.3 2.9
31.6 2.9
26.6 4.8
nd
26.6 2.9
48 9.07
88 14
97 4.04
52 1.5
92.6 3.3
39.5 7.5
111.7 14
105.5 7.5
89.6 2.4
68.3 5.9
62 2.5
38.3 8.2
77 11
124.5 6.5
78 22
>1 ꢁ 10ꢀ5
20.6 11.9
>1 ꢁ 10ꢀ5
>1 ꢁ 10ꢀ5
>1 ꢁ 10ꢀ5
>1 ꢁ 10ꢀ5
>1 ꢁ 10ꢀ5
134 18.7
40.2 29.7
>1 ꢁ 10ꢀ5
88 23
nd
45.7 7.36
nd
nd
nd
nd
nd
52
23.5 0.5
nd
58 15
nd
60.6 5.3
nd
nd
22
2
2
11.2 1.6
12
2
>1 ꢁ 10ꢀ5
16.1 6.1
2.89 1.25
9
1
1.3 0.03
71.4 14
>1 ꢁ 10ꢀ5
4
21.7
9
3.14 0.23
22 12.1
46.2 16.2
26.1 3.6
2.37 1.3
97.7 6.9
>1 ꢁ 10ꢀ5
12.7
5
2
20
nd
nd
42
1
161
9
>1 ꢁ 10ꢀ5
104 57
nd
94.75 10
41.4 2.3
79 12
>1 ꢁ 10ꢀ5
50.8 12.5
nd
nd
63 12
2
26 15
4
Concentration-response curves were analyzed by non-linear regression. Agonist potency was expressed as EC50 (nM) while the maximal efficacy, Emax was expressed as a
percentage of that observed with melatonin 1 M (=100%). Antagonist potency to inhibit the effect of melatonin (30 or 3 nM respectively for MT1 and MT2 receptors) was
expressed as KB. Data are mean of at least 3 independent experiments. nd: not determined.
l

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C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
14-fold, respectively), which gave a derivative with a selectivity ra-
tio of 39. Despite suboptimal selectivity achieved with compounds
35–38, it can be deduced that one of the units of the dimer does not
have to be a melatonin analogue for the heterodimer to retain a
good affinity and selectivity for the MT1 receptor subtype. This con-
clusion confirms our assumption that the dimer does not bridge
two MLT sites but that steric factors are predominantly responsible
for the selectivity of our compounds. For the biphenyl series, an
additional increase in affinity is due to hydrogen bond capable
moiety.
Given that one pharmacophore of the bivalent ligand model
could be replaced by a non-melatoninergic ligand without any loss
of affinity, heterodimers with an agomelatine moiety linked to a
diversely para-substituted biphenyl moiety via a four carbons
chain were prepared (compounds 41–43). As depicted in Table 4,
compounds 42 and 43 possess subnanomolar affinities for MT1
(0.55 and 0.09 nM, respectively) along with selectivity ratios
(MT2/MT1 = 93 and 72, respectively) only slightly lower than that
of the parent compound (4) (MT2/MT1 = 120). These results suggest
that polar interactions might also play a role in the selectivity of
our compounds in addition to steric factors. The hydrogen bound
acceptor (35, 43) appears to contribute to the affinity. Its exact ef-
fect has still to be determined.
performed on a Finnigan MAT SSQ 710 Advantage spectrometer
and were recorded in the APCI positive mode. Elemental analyses
for tested compounds were performed by CNRS Laboratories
(Vernaison, France). Obtained results were within 0.4% of the the-
oretical values.
6.1.1. N-[2-(7-(4-Bromobutoxy)naphthalen-1-yl)ethyl]-
acetamide (14)
A mixture of 8b (6.2 g, 27 mmol) and K2CO3 (18.6 g, 135 mmol)
in acetonitrile (50 mL) was refluxed for 1 h. 1,4-Dibromobutane
(9.7 mL, 81 mmol) was then added dropwise and the mixture
was refluxed for 12 h. The reaction mixture was filtered and the fil-
trate was evaporated under reduced pressure. The residue was dis-
solved in 30 mL of diethyl ether. The organic layer was washed
with water, dried over MgSO4 and evaporated. The residue was
triturated with a mixture of isopropyl ether/petroleum ether
(2:1). After filtration, the precipitate was recrystallized from iso-
propyl ether to give 14 (5.8 g, 15.9 mmol, 59%); mp 65–67 °C; IR
(KBr) 3310 (NH), 1626 (CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6)
;
d 1.83 (s, 3H), 1.88–2.08 (m, 4H), 3.12 (t, J = 7.0 Hz, 2H), 3.34 (m,
2H), 3.67 (m, 2H), 4.22 (m, 2H), 7.16 (dd, J = 8.6 and 2.1 Hz, 1H),
7.22–7.34 (m, 2H), 7.61 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.82 (d,
J = 8.6 Hz, 1H), 8.11 (br s, 1H). Anal. (C18H22BrNO) C, H, N.
In terms of affinity and selectivity, these two compounds seem
interesting and promising as pharmacological tools. Unfortunately,
like the majority of the molecules reported in this paper, they be-
have as partial agonists on MT1 and MT2 melatonin receptors sub-
types. As can also be seen from Table 5, compound 41 is a full
antagonist on the MT1 receptor and five ligands (15, 18, 19, 35
and 37) are full antagonists on MT2 receptors. These compounds
are not of major interest from a pharmacological point of view
due to their partial agonist activity on the other receptor subtype.
The most interesting compounds of this new series of selective
melatoninergic ligands is 36, a full antagonist on both receptor
subtypes with good MT1 and MT2 affinities (0.37 and 4.22 nM,
respectively). However, its weak selectivity (MT2/MT1 ratio 11)
may limit its use as a pharmacological tool. Nevertheless, it is
worth noting that in our binding assay on CHO cells, luzindole, a
melatonin antagonist considered as selective has the same ratio
of selectivity but for the MT2 receptor.3,31
6.1.2. General procedure for the synthesis of heterodimers (15–
17, 19, 22, 35, 36, 41 and 43)
The method adopted for the synthesis of N-[2-(7-{4-[3-(2-acet-
ylaminoethyl)benzofuran-5-yloxy]butoxy}naphthalen-1-yl)ethyl]-
acetamide (15) is described. A mixture of 9b (1.0 g, 4.5 mmol) and
K2CO3 (1.9 g, 14 mmol) in acetonitrile (70 mL) was refluxed for
30 min. 14 (1.64 g, 4.5 mmol) was then slowly added and the mix-
ture was refluxed for 12 h. The solvent was removed under re-
duced pressure, and the residue was washed with a 1 M NaOH
solution. The precipitate was collected by filtration, washed with
water and dried. Recrystallization from acetonitrile gave 15
(1.4 g, 2.8 mmol, 62%); mp 160–162 °C; IR (KBr) 3333 (NH), 1652
(CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) 1.79 (s, 3H), 1.82 (s,
;
3H), 1.92–2.04 (m, 4H), 2.74 (t, J = 6.9 Hz, 2H), 3.11 (t, J = 8.3 Hz,
2H), 3.30–3.34 (m, 4H), 4.12 (m, 2H), 4.27 (m, 2H), 6.92 (dd,
J = 8.9 and 2.2 Hz, 1H), 7.16–7.23 (m, 2H), 7.24–7.34 (m, 2H),
7.43 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 7.8 Hz,
1H), 7.75 (s, 1H), 7.83 (d, J = 9.3 Hz, 1H), 8.00 (br s, 1H), 8.11 (br
s, 1H,). Anal. (C30H34N2O5) C, H, N.
5. Conclusion
We successfully converted a selective MT1 homodimer ligand
into a series of asymmetric dimers with high affinity for melatonin
receptors and selectivity for MT1 ranging between 5- and 93-fold.
Two compounds in this series, 42 and 43, are among the best
MT1-selective derivatives described to date. We have also come
up with an interesting compound 36 for use as a lead molecule
in the development of selective MT1 antagonist. In addition, this
study showed that a bivalent ligand is not necessary to achieve
MT1 selectivity. It also confirmed the importance of a bulky substi-
tuent replacing the methoxy group of compound 1 and helped de-
fine its optimal properties. Compound 43 also hints to a possible
hydrogen bonding capacity helping the affinity of a ligand.
6.1.3. N-[2-(7-{4-[3-(2-Acetylaminoethyl)benzo[b]thiophen-5-
yloxy]butoxy}naphthalen-1-yl)ethyl] acetamide (16)
This compound was prepared from 14 (1.64 g, 4.5 mmol) and
10b (1.06 g, 4.5 mmol) as described for 15. Recrystallization from
acetonitrile/methanol (2:1) gave 16 (1.7 g, 3.3 mmol, 73%); mp
169–170 °C; IR (KBr) 3326 (NH), 1650 (CO) cmꢀ1
;
1H NMR
(300 MHz, DMSO-d6) d 1.80 (s, 3H), 1.82 (s, 3H), 1.95–2.04 (m,
4H), 2.91 (t, J = 7.1 Hz, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.35–3.39 (m,
4H), 4.18 (m, 2H), 4.28 (m, 2H), 7.04 (dd, J = 8.7 and 2.3 Hz, 1H),
7.19 (dd, J = 9.0 and 2.0 Hz, 1H), 7.23–7.32 (m, 2H), 7.41 (d,
J = 2.1 Hz, 1H), 7.44 (s, 1H), 7.62 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H),
7.81–7.84 (m, 2H), 8.04 (br s, 1H), 8.10 (br s, 1H). Anal.
(C30H34N2O4S) C, H, N.
6. Experimental section
6.1. Chemistry
6.1.4. N-[2-(7-{4-[3-(2-Acetylaminoethyl)-1-benzenesulfonyl-1H-
indol-5-yloxy]butoxy}-naphthalen-1-yl)-ethyl]acetamide (17)
This compound was prepared from 14 (1.64 g, 4.5 mmol) and 13
(1.6 g, 4.5 mmol) as described for 15. Recrystallization from etha-
nol gave 17 (1.64 g, 2.56 mmol, 57%); mp 135–137 °C; IR (KBr)
Melting points were determined on a Büchi SMP-20 capillary
apparatus and are uncorrected. IR spectra were recorded on a Vec-
tor 22 Bruker spectrophotometer. 1H NMR spectra were recorded
on an AC 300 Bruker spectrometer. Chemical shifts are reported
in d units (parts per million) relative to TMS. Mass spectra were
3265 (NH), 1640 (CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) d 1.79
;
(s, 3H), 1.81 (s, 3H), 1.88–2.04 (m, 4H), 2.74 (m, 2H), 3.11 (m,

C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
3433
2H), 3.29–3.36 (m, 4H), 4.09 (m, 2H), 4.25 (m, 2H), 6.96 (d,
J = 8.6 Hz, 1H), 7.16–7.30 (m, 4H), 7.78–7.95 (m, 10H), 7.98 (br s,
1H), 8.09 (br s, 1H). Anal. (C36H39N3O6S) C, H, N.
6.1.9. General procedure for the synthesis of amino derivatives
(23 and 28)
The method adopted for the synthesis of N-[2-(7-{4-[8-(2-ami-
noethyl)naphthalen-2-yloxy] butoxy}naphthalen-1-yl)ethyl]acet-
amide hydrochloride (23) is described. A suspension of 22 (0.6 g,
1.1 mmol) in methanol (30 mL) was treated with gaseous HCl.
After stirring for 5 h, the precipitate was collected by filtration
and recrystallized from acetonitrile/methanol (3:1) to give 23
(0.44 g, 0.88 mmol, 80%); mp 188–189 °C; IR (KBr) 3332–2623
6.1.5. N-[2-(7-{4-[3-(2-Acetylaminoethyl)-1H-indol-5-yloxy]-
butoxy}-naphthalen-1-yl)ethyl]acetamide (18)
Magnesium turnings (1.94 g, 80 mmol) and ammonium chlo-
ride (0.18 g, 3.4 mmol) were added to a solution of 17 (1.0 g,
1.5 mmol) in methanol (60 mL). The reaction mixture was stirred
at room temperature for 3 h. A saturated ammonium chloride solu-
tion was added and the reaction mixture was extracted with meth-
ylene chloride. The combined organic layers were dried over
MgSO4 and evaporated under reduced pressure. The solid residue
was recrystallized from ethanol to give 18 (0.45 g, 0.9 mmol,
(NH3+), 1637 (CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) 1.82 (s,
;
3H), 2.01–2.05 (m, 4H), 3.09–3.15 (m, 4H), 3.30–3.35 (m, 4H),
4.27–4.31 (m, 4H), 7.18–7.39 (m, 6H), 7.49 (s, 1H), 7.62 (s, 1H),
7.71 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 9.0 Hz,
1H), 7.87 (d, J = 9.3 Hz, 1H), 8.17–8.24 (m, 4H). Anal.
(C30H34N2O3ꢂHCl) C, H, N.
60%); mp 168–170 °C; IR (KBr) 3268 (NH), 1629 (CO) cmꢀ1 1H
;
NMR (300 MHz, DMSO-d6) d 1.81 (s, 3H), 1.83 (s, 3H), 1.87–2.05
(m, 4H), 2.77 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.3 Hz, 2H), 3.27–3.36
(m, 4H), 4.08 (m, 2H), 4.27 (m, 2H), 6.75 (d, J = 9.1 Hz, 1H), 7.05
(s, 1H), 7.11 (s, 1H), 7.18–7.33 (m, 4H), 7.62 (s, 1H), 7.71 (d,
J = 7.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.94 (br s, 1H), 8.11 (br s,
1H), 10,67 (br s, 1H). Anal. (C30H35N3O4) C, H, N.
6.1.10. General procedure for the synthesis of N-acylated deriv-
atives (24, 25 and 29)
The method adopted for the synthesis of N-[2-(7-{4-[8-(2-Cyclo-
propanecarbonylaminoethyl) naphthalen-2-yloxy]butoxy}naphtha-
len-1-yl)ethyl]acetamide (24) is described. Potassium carbonate
(0.83 g, 6 mmol) was added to a solution of 16 (1 g, 2 mmol) in
water (40 mL) and chloroform (60 mL). After stirring for 20 min at
0 °C, cyclopropanecarbonyl chloride (0.23 mL, 2.2 mmol) was
added dropwise. The reaction mixture was stirred at room temper-
ature for 30 min. The two layers were separated and the organic
layer was washed with 1 M HCl solution and water, dried over
MgSO4 and removed in vacuo. The solid residue was recrystallized
from acetonitrile to give 24 (0.8 g, 1.5 mmol, 75%); mp 154–155 °C;
IR (KBr) 3321 (NH), 1625 (CO), 1636 (CO) cmꢀ1; 1H NMR (300 MHz,
DMSO-d6) 0.61–0.70 (m, 4H), 1.52 (m, 1H), 1.81 (s, 3H), 2.03–2.07
(m, 4H), 3.11–3.14 (m, 4H), 3.30–3.41 (m, 4H), 4.27–4.30 (m, 4H),
7.21 (d, J = 9.0 Hz, 2H), 7.24–7.33 (m, 4H), 7.59 (d, J = 2.0 Hz, 1H),
7.62 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 9.0 Hz,
2H), 8.09 (br s, 1H), 8.29 (br s, 1H). Anal. (C34H38N2O4) C, H, N.
6.1.6. N-[2-(7-{4-[8-(2-Acetylaminoethyl)-5,6,7,8-tetrahydronaph-
thalen-2-yloxy]butoxy} naphthalen-1-yl)ethyl]acetamide (19)
This compound was prepared from 14 (1.64 g, 4.5 mmol) and 11
(1.05 g, 4.5 mmol) as described for 15. Recrystallization from ace-
tonitrile gave 19 (1.53 g, 3 mmol, 66%); mp 63–65 °C; IR (KBr)
3297 (NH), 1654 (CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) 1.56–
;
1.82 (m, 16H), 2.61 (m, 2H), 2.71 (m, 1H), 3.08–3.13 (m, 4H),
3.32 (m, 2H), 4.03 (m, 2H), 4.24 (m, 2H), 6.65–6.74 (m, 2H), 6.93
(d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.9 Hz, J = 1.8 Hz, 1H), 7.23–7.33
(m, 2H), 7.61 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.81–7.88 (m, 2H),
8.11 (br s, 1H). Anal. (C32H40N2O4) C, H, N.
6.1.7. [2-(7-Hydroxynaphthalen-1-yl)-ethyl]carbamic acid tert-
butyl ester (21)
6.1.11. N-[2-(7-{4-[8-(2-(2-Furoyl)aminoethyl)naphthalen-2-
yloxy]butoxy}naphthalen-1-yl}ethyl] acetamide (25)
A mixture of triethylamine (3.88 mL, 280 mmol) and 2-(7-hydrox-
ynaphthalen-1-yl)ethylamine hydrochloride 20 (3.0 g, 11 mmol) in
methylene chloride (60 mL) was stirred for 30 min at 0 °C. A solution
of di-tert-butyldicarbonate (2.3 g, 10 mmol) in methylene chloride
(10 mL) was then added dropwise and the reaction mixture was stir-
red at room temperature for 4 h. The mixture was washed with a
0.1 M HCl solution and water. The organic layer was dried over
MgSO4 and evaporated under reduced pressure. The residue was
recrystallized from cyclohexane/toluene (1:10) to give 21 (2.87 g,
10 mmol, 91%); mp 72–73 °C; IR (KBr) 3409 (OH), 3299 (NH), 1659
This compound was prepared from 23 (1 g, 2 mmol) as de-
scribed for 24 using 2-furoyl chloride (0.22 mL, 2.2 mmol). Recrys-
tallization from acetonitrile gave 25 (0.9 g, 1.6 mmol, 81%); mp
148–149 °C; IR (KBr) 3337 (NH), 1649 (CO), 1624 (CO) cmꢀ1 1H
;
NMR (300 MHz, DMSO-d6) d 1.81 (s, 3H), 2.01–2.06 (m, 4H), 3.11
(t, J = 7.4 Hz, 2H), 3.22 (t, J = 7.4 Hz, 2H), 3.36 (m, 2H), 3.52 (m,
2H), 4.30–4.33 (m, 4H), 6.59 (m, 1H), 7.06 (d, J = 3.6 Hz, 1H),
7.19–7.36 (m, 6H), 7.63 (s, 1H), 7.66 (s, 1H), 7.72–7.74 (m, 2H),
7.82–7.86 (m, 3H), 8.09 (br s, 1H), 8.63 (br s, 1H). Anal.
(C35H36N2O5) C, H, N.
(CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) 1.37 (s, 9H), 3.03 (t,
;
J = 7.2 Hz, 2H), 3.23 (m, 2H), 6.99 (br s, 1H), 7.09 (dd, J = 8.9 and
1.8 Hz, 1H), 7.15–7.24 (m, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.64 (d,
J = 8.0 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 9.74 (br s, 1H). MS m/z: 288.3
[M+H]+.
6.1.12. General procedure for the synthesis of N-acylated
derivatives (26 and 30)
The method adopted for the synthesis of N-[2-(7-{4-[8-(2-viny-
lacetylaminoethyl)naphthalen-2-yloxy]butoxy} naphthalen-1-yl)-
ethyl]acetamide (26) is described. Compound 23 (1.0 g, 2 mmol)
was dissolved in water (50 mL). Sodium hydroxide (0.16 g, 4 mmol)
was added and the reaction mixture was stirred for 1 h at room tem-
perature. The mixture was then extracted with methylene chloride
and dried over MgSO4. Vinylacetic acid (0.29 mL, 3.4 mmol) and N-
(3-dimethylaminopropyl)-N0-ethylcarbodiimide (0.53 g, 3.4 mmol)
were dissolved in methylene chloride (40 mL) at 0 °C. After
30 min, the solution of amine 23 was added dropwise. The reaction
mixture was stirred at 0 °C for 30 min and at room temperature for
1 h; then, it was washed with a 1 M HCl solution and water. The or-
ganic layer was dried over MgSO4, and removed under reduced pres-
sure. The solid residue was recrystallized from acetonitrile to give 26
(0.92 g, 1.72 mmol, 86%); mp 142–143 °C; IR (KBr) 3325 (NH), 1647
6.1.8. [2-(7-{4-[8-(2-Acetylaminoethyl)naphthalen-2-yloxy]-
butoxy}naphthalen-1-yl)ethyl] carbamic acid tert-butyl ester
(22)
This compound was prepared from 14 (1.64 g, 4.5 mmol) and 21
(1.3 g, 4.5 mmol) as described for 15. Recrystallization from tolu-
ene gave 22 (2.06 g, 3.6 mmol, 81%); mp 101–103 °C; IR (KBr)
3330 (NH), 1691 (CO), 1639 (CO) cmꢀ1
;
1H NMR (300 MHz,
DMSO-d6) d 1.37 (s, 9H), 1.81 (s, 3H), 1.99–2.04 (m, 4H), 3.10–
3.13 (m, 4H), 3.20 (m, 2H), 3.32 (m, 2H), 4.28–4.32 (m, 4H), 7.09
(br s, 1H), 7.19 (dd, J = 8.9 Hz and 2.3 Hz, 2H), 7.24–7.33 (m, 4H),
7.63 (s, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H), 8.11
(br s, 1H). Anal. (C35H42N2O5) C, H, N.

3434
C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
(CO), 1626 (CO) cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) 1.81 (s, 3H),
mixture was refluxed for 4 h. The mixture was then removed under
reduced pressure, and the residue was washed with water. After
filtration, the precipitate was washed with petroleum ether and
recrystallized from toluene to give 31b (3.76 g, 18.6 mmol, 81%);
2.01–2.05 (m, 4H), 2.88 (d, J = 7.0 Hz, 2H), 3.09–3.14 (m, 4H),
3.31–3.37 (m, 4H), 4.28–4.32 (m, 4H), 5.02–5.11 (m, 2H), 5.86 (m,
1H), 7.19 (d, J = 9.0 Hz, 2H), 7.23–7.32 (m, 4H), 7.61–7.63 (m, 2H),
7.70–7.72 (m, 2H), 7.81–7.84 (m, 2H), 8.07 (br s, 2H). Anal.
(C34H38N2O4) C, H, N.
mp 151–152 °C; IR (KBr) 3298 (OH), 1709 (CO) cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6) 3.91 (s, 2H), 7.08 (dd, J = 8.8 Hz, J = 2.2 Hz,
1H), 7.12–7.24 (m, 2H), 7.33 (m, 1H), 7.71 (m, 1H), 7.79 (d,
J = 8.8 Hz, 1H), 9.28 (br s, 1H), 12.39 (br s, 1H). MS m/z: 203.2
[M+H]+.
6.1.13. N-[2-(7-{4-[8-(2-tert-Butoxycarbonylaminoethyl)-
naphthalen-2-yloxy]butoxy} naphthalen-1-yl)ethyl]carbamic
acid tert-butyl ester (27)
A mixture of 21 (0.72 g, 2.5 mmol) and K2CO3 (0.83 g, 6 mmol)
in acetonitrile (50 mL) was refluxed for 1 h. 1,4-Dibromobutane
(0.12 mL, 1 mmol) was then added dropwise and the mixture
was refluxed for 4 h. The mixture was filtered and the filtrate
was evaporated under reduced pressure. The residue was dissolved
in diethyl ether and the organic layer was washed with water,
dried over MgSO4 and evaporated. The residue was recrystallized
from acetonitrile to give 27 (1.07 g, 1.7 mmol, 68%); mp 139–
6.1.18. 2-(6-Hydroxynaphthalen-2-yl)propionic acid (32b)
This compound was prepared from 2-(6-methoxynaphtalen-2-
yl)propionic acid (32a) (5 g, 21 mmol) using hydrobromic acid
47% (23 mL) as described for 31b. Recrystallization from toluene
gave 32b (3.9 g, 18.3 mmol, 87%); mp 188–189 °C; IR (KBr) 3348
(OH), 2984 (OH), 1713 (CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6)
;
1.43 (d, J = 7.0 Hz, 3H), 3.76 (m, 1H), 7.06–7.09 (m, 2H), 7.33 (dd,
J = 8.6 Hz, J = 1.6 Hz, 1H), 7.63–7.66 (m, 2H), 7.73 (d, J = 8.6 Hz,
1H), 9.71 (br s, 1H), 12.31 (br s, 1H). MS m/z: 217.2 [M+H]+.
140 °C; IR (KBr) 3409 (NH), 1711 (CO) cmꢀ1 1H NMR (300 MHz,
;
DMSO-d6) d 1.37 (s, 18H), 2.06 (m, 4H), 3.13 (m, 4H), 3.20 (m,
4H), 4.30 (m, 4H), 7.09 (br s, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.23–
7.31 (m, 4H), 7.63 (s, 2H), 7.70 (d, J = 7.7 Hz, 2H), 7.83 (d,
J = 8.7 Hz, 2H). Anal. (C38H48N2O6) C, H, N.
6.1.19. General procedure for the synthesis of methylic esters
(33 and 34)
The method adopted for the synthesis of (7-hydroxynaphtha-
len-1-yl)acetic acid methyl ester (33) is described. Thionyl chloride
(3.24 mL, 44.4 mmol) was slowly added to a solution of 31 (3 g,
14.8 mmol) in methanol (50 mL) at 0 °C. The mixture was kept at
0 °C for 20 min and stirred at room temperature for 1 h. The meth-
anol was removed under reduced pressure and the residue was
recrystallized from cyclohexane/toluene (1:4) to give 33 (2.78 g,
12.9 mmol, 87%); mp 115–116 °C; IR (KBr) 3298 (OH), 1716
6.1.14. 2-[7-(4-{8-(2-Aminoethyl)naphthalen-2-yloxy}butoxy)-
naphthalen-1-yl]ethylamine dihydrochloride (28)
This compound was prepared from 27 (0.7 g, 1.1 mmol) using
gaseous HCl as described for 23. Recrystallization from acetonitrile
gave 28 (0.41 g, 0.82 mmol, 75%); mp >240 °C; IR (KBr) 2363–3140
(NH3+) cmꢀ1; 1H NMR (300 MHz, DMSO-d6) d 2.03 (m, 4H), 3.06 (m,
4H), 3.38 (m, 4H), 4.32 (m, 4H), 7.23 (d, J = 8.9 Hz, 2H), 7.29 (t,
J = 7.3 Hz, 2H), 7.38 (d, J = 7.0 Hz, 2H), 7.52 (s, 2H), 7.76 (d,
J = 8.1 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H), 8.33 (br s, 6H). Anal.
(C28H32N2O2ꢂ2HCl) C, H, N.
(CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) 3.63 (s, 3H), 4.01 (s,
;
2H), 7.11 (dd, J = 9.0 Hz, J = 2.2 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H),
7.22 (m, 1H), 7.35 (m, 1H), 7.73 (m, 1H), 7.78 (d, J = 9.0 Hz, 1H),
9.08 (br s, 1H). MS m/z: 217.23 [M+H]+.
6.1.15. N-[2-(7-{4-[8-(2-Cyclopropylcarbonylaminoethyl)-
naphthalen-2-yloxy]butoxy} naphthalen-1-
6.1.20. 2-(6-Hydroxynaphthalen-2-yl)propionic acid methyl
ester (34)
yl)ethyl]cyclopropylcarboxamide (29)
This compound was prepared from 32 (3 g, 14 mmol) using
thionyl chloride (3.04 ml, 41.7 mmol) as described for 33. Recrys-
tallization from cyclohexane gave 34 (2.35 g, 10.2 mmol, 73%);
This compound was prepared from 28 (1 g, 2 mmol), using
cyclopropanecarbonyl chloride (0.46 mL, 5 mmol) and potassium
carbonate (1.65 g, 12 mmol) as described for 24. Recrystallization
from acetonitrile gave 29 (0.89 g, 1.58 mmol, 79%); mp 177–
mp 81–82 °C; IR (KBr) 3367 (OH), 1708 (CO) cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6) 1.45 (d, J = 7.0 Hz, 3H), 3.59 (s, 3H), 3.88 (m,
1H), 7.06–7.09 (m, 2H), 7.3 (dd, J = 8.6 Hz, J = 1.6 Hz, 1H), 7.64–
7.65 (m, 2H), 7.73 (d, J = 8.6 Hz, 1H), 9.71 (br s, 1H). MS m/z:
231.3 [M+H]+.
179 °C; IR (KBr) 3313 (NH), 1638 (CO) cmꢀ1 1H NMR (300 MHz,
;
DMSO-d6) 0.61–0.70 (m, 8H), 1.52 (m, 2H), 2.03 (m, 4H), 3.12 (t,
J = 7.4 Hz, 4H), 3.38 (m, 4H), 4.29 (m, 4H), 7.21 (d, J = 8.7 Hz, 2H),
7.25–7.34 (m, 4H), 7.61 (s, 2H), 7.72 (d, J = 7.6 Hz, 2H), 7.83 (d,
J = 8,7 Hz, 2H), 8.29 (br s, 2H). Anal. (C36H40N2O4ꢂ1/2H2O) C, H, N.
6.1.21. N-[2-(7-{4-[8-(Methoxycarbonylmethyl)naphthalen-2-
yloxy]butoxy}naphthalen-1-yl)ethyl] acetamide (35)
6.1.16. N-[2-(7-{4-[8-(2-Vinylacetylaminoethyl)naphthalen-2-
yloxy]butoxy}naphthalen-1-yl)ethyl]vinylacetamide (30)
This compound was prepared from 28 (1 g, 2 mmol) using
vinylacetic acid (0.58 mL, 6.8 mmol) as described for 26. Recrystal-
lization from acetonitrile gave 30 (0.74 g, 1.32 mmol, 66%); mp
This compound was prepared from 14 (1.67 g, 4.6 mmol) and 33
(1 g, 4.6 mmol) as described for 15. Recrystallization from metha-
nol gave 35 (1.77 g, 3.54 mmol, 77%); mp 109–110 °C; IR (KBr)
3331 (NH), 1727 (CO), 1632 (CO) cmꢀ1
;
1H NMR (300 MHz,
DMSO-d6) 1.82 (s, 3H), 2.01–2.04 (m, 4H), 3.12 (t, J = 7.3 Hz, 2H),
3.33 (m, 2H), 3.60 (s, 3H), 4.11 (s, 2H), 4.22 (m, 2H), 4.29 (m,
2H), 7.02–7.33 (m, 6H), 7.39 (d, J = 6.1 Hz, 1H), 7.63 (d, J = 1.9 Hz,
1H), 7.71 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.82–7.88 (m,
2H), 8.10 (br s, 1H). Anal. (C31H33NO5) C, H, N.
146–148 °C; IR (KBr) 3328 (NH), 1645 (CO) cmꢀ1
;
1H NMR
(300 MHz, DMSO-d6) 2.05 (m, 4H), 2.88 (d, J = 6.9 Hz, 4H), 3.12 (t,
J = 7.4 Hz, 4H), 3.35 (m, 4H), 4.30 (m, 4H), 5.02–5.11 (m, 4H),
5.85 (m, 2H), 7.20 (dd, J = 9.0 and 2.0 Hz, 2H), 7.22–7.31 (m, 4H),
7.61 (d, J = 2.0 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 9.0 Hz,
2H), 8.07 (br s, 2H). Anal. (C36H40N2O4) C, H, N.
6.1.22. N-[2-(7-{4-[6-(1-Methoxycarbonylethyl)naphthalen-2-
yloxy]butoxy}naphthalen-1-yl)ethyl] acetamide (36)
6.1.17. General procedure for the synthesis of phenolic deriva-
tives (31b and 32b)
The method adopted for the synthesis of (7-hydroxynaphtha-
len-1-yl)acetic acid (31b) is described. To a solution of (7-meth-
oxynaphthalen-1-yl)acetic acid (31a) (5 g, 23 mmol) in acetic
acid (50 mL) was added hydrobromic acid 47% (25 mL) and the
This compound was prepared from 14 (1.64 g, 4.5 mmol) and 34
(1.03 g, 4.5 mmol) as described for 15. Recrystallization from tolu-
ene give 36 (1.15 g, 2.25 mmol, 50%); mp 116–117 °C; IR (KBr)
3276 (NH), 1735 (CO), 1637 (CO) cmꢀ1
;
1H NMR (300 MHz,
DMSO-d6) 1.50 (d, J = 7.3 Hz, 3H), 1.82 (s, 3H), 2.01–2.04 (m, 4H),
3.12 (m, 2H), 3.37 (m, 2H), 3.62 (s, 3H), 4.11 (q, J = 7.3 Hz, 1H),

C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
3435
4.22 (m, 2H), 4.29 (m, 2H), 7.15–7.20 (m, 2H), 7.22–7.33 (m, 3H),
7.38 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.68–
7.76 (m, 4H), 7.80–7.85 (m, 2H). Anal. (C32H35NO5) C, H, N.
(KBr) 3313 (OH), 1728 (CO), 1638 (CO) cmꢀ1
;
1H NMR (300 MHz,
DMSO-d6) 1.82 (s, 3H), 1.95–2.03 (m, 4H), 3.11 (t, J = 7.2 Hz, 2H),
3.32 (m, 2H), 3.87 (s, 3H), 4.15 (m, 2H), 4.27 (m, 2H), 7.08 (d,
J = 8.6 Hz, 2H), 7.18 (dd, J = 8.9 Hz, J = 2.1 Hz, 1H), 7.24–7.32 (m,
2H), 7.63 (s, 1H), 7.68–7.73 (m, 3H), 7.77–7.84 (m, 3H), 8.01 (d,
J = 8.2 Hz, 2H), 8.11 (br s, 1H). Anal. (C32H33NO5) C, H, N.
6.1.23. General procedure for the synthesis of carboxy
derivatives (37, 38, and 42)
The method adopted for the synthesis of N-[2-{7-(4-[8-(car-
boxymethyl)naphthalen-2-yloxy] butoxy) naphthalen-1-yl}ethyl
]acetamide (37) is described. To a solution of 35 (1 g, 2 mmol) in
THF (25 mL) and methanol (15 mL) was added a solution of sodium
hydroxide (0.24 g, 6 mmol) in water (15 mL). The mixture was stir-
red at room temperature for 4 h. After concentration under re-
duced pressure, the mixture was acidified with 1 M HCl. The
precipitate was then collected by filtration and recrystallized from
methanol to give 37 (0.65 g, 1.34 mmol, 67%); mp 131–132 °C; IR
6.1.28. N-[2-(7-{4-(40-Carboxybiphenyl-4-yloxy)butoxy}-
naphthalen-1-yl)ethyl]acetamide (42)
This compound was prepared from 41 (1 g, 1.9 mmol) using so-
dium hydroxide (0.23 g, 5.7 mmol) as described for 37. Recrystalli-
zation from DMF gave 42 (0.56 g, 1.14 mmol, 60%); mp 223–
225 °C; IR (KBr) 3301 (NH), 2952 (OH), 1674 (CO), 1625 (CO) cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) 1.82 (s, 3H), 1.95–2.03 (m, 4H), 3.11
(t, J = 7.2 Hz, 2H), 3.31 (m, 2H), 4.16 (m, 2H), 4.28 (m, 2H), 7.09 (d,
J = 8.7 Hz, 2H), 7.17 (dd, J = 9.2 Hz, J = 2.3 Hz, 1H), 7.20–7.33 (m,
2H), 7.62 (s, 1H), 7.68–7.73 (m, 5H), 7.84 (d, J = 9.2 Hz, 1H), 7.99
(d, J = 8.2 Hz, 2H), 8.13 (br s, 1H), 11.98 (br s, 1H). Anal.
(C31H31NO5) C, H, N.
(KBr) 3329 (NH), 2933 (OH), 1697 (CO), 1629 (CO) cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6) 1.83 (s, 3H), 2.01–2.04 (m, 4H), 3.12 (t,
J = 7.3 Hz, 2H), 3.34 (m, 2H), 4.00 (s, 2H), 4.21 (m, 2H), 4.29 (m,
2H), 7.19–7.34 (m, 6H), 7.39 (d, J = 7.0 Hz, 1H), 7.63 (s, 1H), 7.72
(d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.82–7.88 (m, 2H), 8.10
(br s, 1H), 12.44 (br s, 1H). Anal. (C30H31NO5) C, H, N.
6.1.29. N-[2-(7-{4-(40-Hydroxymethylbiphenyl-4-yloxy}butoxy)-
naphthalen-1-yl)ethyl]acetamide (43)
6.1.24. N-[2-(7-{4-[6-(1-Carboxyethyl)naphthalen-2-yloxy]-
butoxy}naphthalen-1-yl)ethyl]acetamide (38)
This compound was prepared from 36 (1 g, 1.9 mmol) using so-
dium hydroxide (0.023 g, 5.7 mmol) as described for 37. Recrystal-
lization from toluene gave 38 (0.39 g, 0.78 mmol, 41%); mp 142–
This compound was prepared from 14 (1.82 g, 5 mmol) and 40
(1 g, 5 mmol) as described for 15. Recrystallization from acetoni-
trile give 43 (1.33 g, 2.75 mmol, 55%); mp 172–173 °C; IR (KBr)
3331 (NH, OH), 1643 (CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6)
;
1.83 (s, 3H), 1.97–2.05 (m, 4H), 3.11 (t, J = 7.2 Hz, 2H), 3.33 (m,
2H), 4.13 (m, 2H), 4.27 (m, 2H), 4.52 (d, J = 5.5 Hz, 2H), 5.20 (t,
J = 5.5 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.17 (dd, J = 9.0 Hz,
J = 2.3 Hz, 1H), 7.19–7.30 (m, 4H), 7.55–7.59 (m, 4H), 7.62 (d,
J = 2.3 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H),
8.12 (br s, 1H). Anal. (C31H33NO4) C, H, N.
143 °C; IR (KBr) 3274 (NH) 2874 (OH), 1704 (CO), 1627 (CO) cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) 1.44 (d, J = 7.3 Hz, 3H), 1.82 (s, 3H),
2.00–2.05 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 3.35 (m, 2H), 3.78 (q,
J = 7.3 Hz, 1H), 4.20 (m, 2H), 4.28 (m, 2H), 7.14–7.21 (m, 2H),
7.23–7.34 (m, 3H), 7.38 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.68–7.76
(m, 3H), 7.80–7.85 (m, 2H), 8.12 (br s, 1H), 12.33 (br s, 1H). Anal.
(C31H33NO5) C, H, N.
6.2. Pharmacological methods
6.1.25. 40-Hydroxy[1,10-biphenyl]-4-carboxylic acid methyl ester
(39)
6.2.1. Reagents and chemicals
2-[125I]-Iodomelatonin (2200 Ci/mmol) was purchased from
NEN (Boston, MA). Other drugs and chemicals were purchased
from Sigma–Aldrich (Saint Quentin, France).
This compound was prepared from 4-(40-hydroxyphenyl)ben-
zoic acid (3 g, 14 mmol) using thionyl chloride (3.1 mL, 42 mmol)
as described for 33. Recrystallization from acetonitrile gave 39
(2.4 g, 10.5 mmol, 75%); mp 231–233 °C; IR (KBr) 3401 (OH),
1689 (CO) cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) 3.86 (s, 3H), 6.88
6.2.2. Cell culture
(dd, J = 6.8 Hz, J = 1.9 Hz, 2H), 7.58 (dd, J = 6.8 Hz, J = 1.9 Hz, 2H),
7.73 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 9.76 (br s, 1H). MS
m/z: 229.2 [M+H]+.
CHO cell lines stably expressing the human melatonin MT1 or
MT2 receptors were grown in DMEM medium supplemented with
10% fetal calf serum, 2 mM glutamine, 100 IU/mL penicillin and
100 lg/mL streptomycin. Grown at confluence at 37 °C (95% O2/
6.1.26. 40-Hydroxy[1,10-biphenyl]-4-methanol (40)
5% CO2), they were harvested in PBS containing EDTA 2 mM and
centrifuged at 1000g for 5 min (4 °C). The resulting pellet was sus-
pended in TRIS 5 mM (pH 7.5), containing EDTA 2 mM and homog-
enized using a Kinematica polytron. The homogenate was then
centrifuged (95,000g, 30 min, 4 °C) and the resulting pellet sus-
pended in 75 mM TRIS (pH 7.5), 12.5 mM MgCl2 and 2 mM EDTA.
Aliquots of membrane preparations were stored at ꢀ80 °C until
use.
To a suspension of LiAlH4 (1.14 g, 30 mmol) in THF (80 mL) at
0 °C was added dropwise a solution of 39 (3.3 g, 15 mmol) in dry
THF (30 mL). The reaction mixture was stirred 30 min. at 0 °C
and 48 h at room temperature. The mixture was then cooled down
with an ice bath and water (1.1 mL) was added, followed by a 15%
NaOH aqueous solution (1.1 mL) and water (2.2 mL). The mixture
was filtered and the solid was washed with ether. The filtrate
was evaporated and the crude product was recrystallized from tol-
uene to give 40 (2.28 g, 11.4 mmol, 76%); mp 198–199 °C; IR (KBr)
6.2.3. Binding assays
3387 (OH) cmꢀ1
;
1H NMR (300 MHz, DMSO-d6) 4.51 (d, J = 5.3 Hz,
2-[125I]-iodomelatonin binding assay conditions were essen-
tially as previously described.31 Briefly, binding was initiated by
addition of membrane preparations from stable transfected CHO
cells diluted in binding buffer (50 mM Tris/HCl buffer, pH 7.4 con-
taining 5 mM MgCl2) to 2-[125I]-iodomelatonin (20 pM for MT1 and
MT2 receptors) and the tested drug. Nonspecific binding was de-
2H), 5.19 (m, 1H), 6.85 (dd, J = 6.8 Hz, J = 1.9 Hz, 2H), 7.34 (dd,
J = 6.8 Hz, J = 1.9 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.98 (d,
J = 8.4 Hz, 2H), 9.53 (br s, 1H). MS m/z: 201.3 [M+H]+.
6.1.27. N-[2-(7-{4-[40-Methoxycarbonylbiphenyl-4-yloxy]-
butoxy}naphthalen-1-yl)ethyl] acetamide (41)
fined in the presence of 1 lM melatonin. After 120 min incubation
This compound was prepared from 14 (1.64 g, 4.5 mmol) and 39
(1.02 g, 4.5 mmol) as described for 15. Recrystallization from ace-
tonitrile give 41 (1.63 g, 3.2 mmol, 71%); mp 166–168 °C; IR
at 37 °C, reaction was stopped by rapid filtration through GF/B fil-
ters presoaked in 0.5% (v/v) polyethylenimine. Filters were washed
three times with 1 ml of ice-cold 50 mM Tris/HCl buffer, pH 7.4.

3436
C. Mésangeau et al. / Bioorg. Med. Chem. 18 (2010) 3426–3436
10. Mazzucchelli, C.; Pannacci, M.; Nonno, R.; Lucini, V.; Fraschini, F.; Stankov, B.
Data from the dose–response curves (seven concentrations in
M. Brain Res. Mol. Brain Res. 1996, 39, 117.
11. Ting, K. N.; Blaylock, N. A.; Sugden, D.; Delagrange, P.; Scalbert, E.; Wilson, V. G.
Br. J. Pharmacol. 1999, 127, 987.
12. Dubocovich, M. L. Trends Pharmacol. Sci. 1995, 16, 50.
13. Nosjean, O.; Ferro, M.; Coge, F.; Beauverger, P.; Henlin, J. M.; Lefoulon, F.;
Fauchère, J. L.; Delagrange, P.; Canet, E.; Boutin, J. A. J. Biol. Chem. 2000, 275,
31311.
14. Nosjean, O.; Nicolas, J. P.; Klupsch, F.; Delagrange, P.; Canet, E.; Boutin, J. A.
Biochem. Pharmacol. 2001, 61, 1369.
duplicate) were analysed using the program PRISM (Graph Pad
Software Inc., San Diego, CA) to yield IC50 (inhibitory concentration
50). Results are expressed as Ki = IC50/1 + ([L]/KD), where [L] is the
concentration of radioligand used in the assay and KD, the dissoci-
ation constant of the radioligand characterising the membrane
preparation.
[
35S]-GTP
cS binding assay was performed according to pub-
15. Spadoni, G.; Balsamini, C.; Bedini, A.; Diamantini, G.; Di Giacomo, B.; Tontini,
A.; Tarzia, G. J. Med. Chem. 1998, 41, 3624.
lished methodology.31 Briefly, membranes from transfected CHO
cells expressing MT1 or MT2 receptor subtype and compounds
were diluted in binding buffer (20 mM HEPES, pH 7.4, 100 mM
16. Spadoni, G.; Balsamini, C.; Diamantini, G.; Tontini, A.; Tarzia, G.; Mor, M.;
Rivara, S.; Plazzi, P. V.; Nonno, R.; Lucini, V.; Pannacci, M.; Fraschini, F.;
Stankov, B. M. J. Med. Chem. 2001, 44, 2900.
17. Faust, R.; Garratt, P. J.; Jones, R.; Yeh, L. K.; Tsotinis, A.; Panoussopoulou, M.;
Calogeropoulou, T.; Teh, M. T.; Sugden, D. J. Med. Chem. 2000, 43, 1050.
18. Jellimann, C.; Mathe-Allainmat, M.; Andrieux, J.; Kloubert, S.; Boutin, J. A.;
Nicolas, J. P.; Bennejean, C.; Delagrange, P.; Langlois, M. J. Med. Chem. 2000, 43,
4051.
NaCl, 3
was started by the addition of 0.2 nM [35S]-GTP
(20 g/ml) and drugs, and further followed for 1 h at room temper-
l
M GDP, 3 mM MgCl2, and 20
l
g/ml saponin). Incubation
c
S to membranes
l
ature. For experiments with antagonists, membranes were pre-
incubated with both the melatonin (30 or 3 nM for hMT1 and
hMT2 receptors, respectively) and the antagonist for 30 min prior
19. Mor, M.; Spadoni, G.; Di Giacomo, B.; Diamantini, G.; Bedini, A.; Tarzia, G.;
Plazzi, P. V.; Rivara, S.; Nonno, R.; Lucini, V.; Pannacci, M.; Fraschini, F.;
Stankov, B. M. Bioorg. Med. Chem. 2001, 9, 1045.
20. Wallez, V.; Durieux-Poissonnier, S.; Chavatte, P.; Boutin, J. A.; Audinot, V.;
Nicolas, J. P.; Bennejean, C.; Delagrange, P.; Renard, P.; Lesieur, D. J. Med. Chem.
2002, 45, 2788.
the addition of [35S]-GTP
cold GTP S (10
c
S. Non specific binding was defined using
lM). Reaction was stopped by rapid filtration
c
through GF/B filters followed by three successive washes with
21. Yous, S.; Durieux-Poissonnier, S.; Lipka-Belloli, E.; Guelzim, H.; Bochu, C.;
Audinot, V.; Boutin, J. A.; Delagrange, P.; Bennejean, C.; Renard, P.; Lesieur, D.
Bioorg. Med. Chem. 2003, 11, 753.
ice-cold buffer.
Usual levels of [35S]-GTP
c
S binding (expressed in dpm) were for
CHO-MT2 membranes: 2000 for basal activity, 8000 in the presence
of melatonin 1 M and 180 in the presence of GTP S 10 M which
22. Rivara, S.; Mor, M.; Silva, C.; Zuliani, V.; Vacondio, F.; Spadoni, G.; Bedini, A.;
Tarzia, G.; Lucini, V.; Pannacci, M.; Fraschini, F.; Plazzi, P. V. J. Med. Chem. 2003,
46, 1429.
l
c
l
defined the non specific binding. Data from the dose–response
curves (seven concentrations in duplicate) were analysed by using
the program PRISM (Graph Pad Software Inc., San Diego, CA) to
yield EC50 (Effective concentration 50%) and Emax (maximal effect)
for agonists. Antagonist potencies are expressed as KB = IC50
1 + ([Ago]/EC50 ago), where IC50 is the inhibitory concentration of
antagonist that gives 50% inhibition of [35S]-GTP
S binding in the
presence of a fixed concentration of melatonin ([Ago]) and EC50
ago is the EC50 of the molecule when tested alone. Imax (maximal
inhibitory effect) was expressed as a percentage of that observed
with melatonin 30 or 3 nM for hMT1 and hMT2 receptors,
respectively.
23. Lucini, V.; Pannacci, M.; Scaglione, F.; Fraschini, F.; Rivara, S.; Mor, M.; Bordi, F.;
Plazzi, P.-V.; Spadoni, G.; Bedini, A.; Piersanti, G.; Diamantini, G.; Tarzia, G. J.
Med. Chem. 2004, 47, 4202.
24. Rivara, S.; Lorenzi, S.; Mor, M.; Plazzi, P. V.; Spadoni, G.; Bedini, A.; Tarzia, G. J.
Med. Chem. 2005, 48, 4049.
25. Bedini, A.; Spadoni, G.; Gatti, G.; Lucarini, S.; Tarzia, G.; Rivara, S.; Lorenzi, S.;
Lodola, A.; Mor, M.; Lucini, V.; Pannacci, M.; Scaglione, F. J. Med. Chem. 2006, 49,
7393.
/
c
26. Rivara, S.; Lodola, A.; Mor, M.; Bedini, A.; Spadoni, G.; Lucini, V.; Pannacci, M.;
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27. Zlotos, D. P.; Attia, M. I.; Julius, J.; Sethi, S.; Witt-Enderby, P. A. J. Med. Chem.
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28. Leclerc, V.; Yous, S.; Delagrange, P.; Boutin, J. A.; Renard, P.; Lesieur, D. J. Med.
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29. Tsotinis, A.; Afoudakis, P. A. Lett. Org. Chem. 2008, 5, 507–509.
30. Dubocovich, M. L.; Masana, M. I.; Iacob, S.; Sauri, D. M. Naunyn-Schmiedeberg’s
Arch. Pharmacol. 1997, 355, 365.
Acknowledgments
31. Audinot, V.; Mailliet, F.; Lahaye-Brasseur, C.; Bonnaud, A.; Le Gall, A.; Amossé,
C.; Dromaint, S.; Rodriguez, M.; Nagel, N.; Galizzi, J. P.; Malpaux, B.;
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46, 1127.
The authors gratefully acknowledge the technical assistance of
Mrs. Anne Bonnaud and Mr. Michael Spedding. The 300 MHz
NMR facilities were funded by the Région Nord-Pas de Calais
(France), the Ministère de la Jeunesse, de l’Education Nationale et
de la Recherche (MJENR) and the Fonds Européens de Développe-
ment Régional (FEDER).
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Supplementary data
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M. QSAR 1999, 18, 561.
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Supplementary data associated with this article can be found, in
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