Design, synthesis, and biological evaluation of a new class of MT 2-selective agonists

Article abstract of DOI:10.1039/c4ra03728f

A novel class of chiral 2,3-dihydro-1H-indene derivatives were designed and synthesized as melatonergic ligands. Most of the reported MT ₂-selective ligands behave as antagonists. By contrast, our exploration of 2,3-dihydro-1H-indene showed that the introduction of a lipophilic group at the 2- or 3-position of this scaffold could afford highly selective MT₂ agonists. Among all these synthesized molecules, compounds 10b, 12a, 17a, 20a exhibited powerful MT₂ agonistic activity (EC₅₀ < 50 nM) as well as excellent MT₂ selectivity (more than 2200-fold). the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra03728f

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Design, synthesis, and biological evaluation of a
new class of MT2-selective agonists†
Cite this: RSC Adv., 2014, 4, 25871
a
b
a
a
b
a
*
*
Xuan Zhang, Zhilong Wang, Qingqing Huang, Yu Luo, Xin Xie and Wei Lu
A novel class of chiral 2,3-dihydro-1H-indene derivatives were designed and synthesized as melatonergic
ligands. Most of the reported MT2-selective ligands behave as antagonists. By contrast, our exploration
of 2,3-dihydro-1H-indene showed that the introduction of a lipophilic group at the 2- or 3-position of
this scaffold could afford highly selective MT2 agonists. Among all these synthesized molecules,
compounds 10b, 12a, 17a, 20a exhibited powerful MT2 agonistic activity (EC50 < 50 nM) as well as
excellent MT2 selectivity (more than 2200-fold).
Received 24th April 2014
Accepted 3rd June 2014
DOI: 10.1039/c4ra03728f
www.rsc.org/advances
insomnia in 2005.18–20 Agomelatine, a melatonin receptor
agonist (MT1 and MT2) and selective serotonin receptor antag-
onist (5-HT2c),21 has been approved by the European Medicines
Agency in 2009 for major depressive disorder. It could relieve
the symptoms of major depression and meanwhile, it enhances
sleep quality in depressed patients.22
Up to date, most of the melatonin receptor agonists are non-
selective and only a few MT2-selective ligands have been
reported.23–30 However, most of these molecules behave as
antagonists, the representative compounds luzindole and 4-
phenyl-2-propionamidotetralin (4P-PDOT) block the MLT-
mediated phase advances of circadian rhythms in mice. More-
over, an antidepressive effect has been reported for luzindole in
a mice model, being ascribed to its selective action at the MT2
receptor.31,32 In addition, an accurate characterization of MLT
receptors-mediated functions can only be obtained by using
subtype-selective ligands. Koike et al. reported the most
Introduction
Melatonin (5-methoxy-N-acetyltryptamine, MLT, Fig. 1) is a
neurohormone synthesized and secreted from the pineal gland
of mammals including humans.1 MLT plays an important role
in modulation of the sleep–wake cycle and circadian rhythms in
humans.2 Other reported effects of MLT include its anti-
inammatory,3 pain modulatory,4 retinal,5 vascular,6 anti-
tumor,7–9 antioxidant,10 strokeprotective11 and neuroprotective
roles.12,13 In mammals, MLT exerts its physiological effects
mainly through the activation of the high affinity G-protein-
coupled receptors MT1 and MT2.14 It is known that MT1 recep-
tors are expressed in several areas such as brain, especially in
the suprachiasmatic nuclei (SCN) as well as the pars tuberalis of
pituitary and might be implicated in the sleep promoting effects
of MLT and in mediating vasoconstriction, whereas MT2
receptors are localized in the SCN and retina, and appear to play
a major role in the resynchronizing activity of MLT and in
mediating vasodilation.
A large number of studies regarding the treatment of circa-
dian rhythm disorders reported that the efficacy of MLT is
always limited by the unfavorable pharmacokinetic prole such
as short half-life in the human body.15 Over the last twenty
years, many melatonin receptor agonists with improved prop-
erties in comparison to MLT have been published.16,17 Takeda
Pharmaceuticals North America developed ramelteon with a
longer half-life, which was approved by FDA for the treatment of
aInstitute of Drug Discovery and Development, Shanghai Engineering Research Center
of Molecular Therapeutics and New Drug Development, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P.R. China. E-mail: wlu@chem.ecnu.
edu.cn; Fax: +86 21 62602475
bCAS Key Laboratory of Receptor Research, National Center for Drug Screening,
Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai
201203, P.R. China. E-mail: xxie@mail.shcnc.ac.cn
† Electronic supplementary information (ESI) available: Details of experimental
procedure, spectral data of all novel compounds. See DOI: 10.1039/c4ra03728f
Fig. 1 Representative melatonin receptor ligands.
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efficient MT2-selective agonist 1 as it shows 1200-fold higher group gave indanol 7. Gabriel reaction involving the mesylated
affinity for the MT2 than the MT1 receptor.33
form of compound 7 followed by acylation of the corresponding
Current SAR of indan derivatives disclosed that the chiral amine 9 in the presence of anhydride furnished chiral amide 10.
centre is essential for melatonin receptor affinity. For example, Then the key ketone intermediate 11 was obtained in an
compound 2 (S-enantiomer) showed over 700 times higher excellent ee value (>99%) aer dithiane deprotection with
affinity than its R-enantiomer (Ki ¼ 0.041 nM vs. Ki ¼ 30.1 nM).19 AgNO3. Finally, the cyclic ketones 11 underwent aldol conden-
However, the previous reported works are mainly focused on sation with the required aldehyde in the presence of MeONa to
achiral molecules.17,34,35 More recently we have reported an give the designed molecules 12–20.38
efficient synthesis of chiral indan derivatives.36 By introducing
Theoretically, the E- and Z-geometric isomers can be equally
lipophilic groups to 2- or 3-position of the indan core, we formed in the above mentioned aldol condensation. However,
attempted to prepare novel melatonergic ligands with improved only the E-isomers were obtained, most probably due to strong
MT2-selectivity and blood–brain barrier permeability.33,37
steric interaction between the aryl/alkyl and carbonyl groups.
Herein we report novel 2,3-dihydro-1H-indene derivatives as The appearance of the “diagnostic” vinyl proton signal in the
highly selective MT2 agonists. The chiral centre of ramelteon appropriate range (7.70–7.50 ppm for aryl enones 12–18 and
was preserved and a variety of lipophilic groups were introduced 7.00–6.90 for alkyl enones 19–20) in the 1H NMR spectra
on the non-aromatic indan cycle. The preliminary conclusions unambiguously corroborated their E conguration.39 This
regarding structure–activity relationships are discussed.
assignment was further conrmed by key NOESY interactions
(see ESI† compound 18b) and is consistent with observations
made with this reaction in similar substrates.40–45
Result and discussion
Chemistry
Biological evaluation
The general route used for the synthesis of the target indan The intrinsic potency of these compounds was evaluated using
derivatives is depicted in Scheme 1. Following previously HTRF IP-One Terbium-based assay and the results are depicted
reported procedures, chiral indanone 3 can be easily prepared in Table 1. Compared to full agonist ramelteon and its strict
from (E)-3-(3-methoxyphenyl)acrylaldehyde.36 Subsequently, methoxy analogue 2 (EC50 (MT1) ¼ 0.36 nM; EC50 (MT2) ¼ 0.97
compound 3 was subjected to hydrolysis, decarboxylation and nM), the oxo derivatives 11a (or 11b) showed moderate potency
esterication to afford chiral ester 5 with a global yield of 48%. at both subtypes and slight preference for MT2 (MT1/MT2 ¼ 8–
Treatment of compound 5 with ethane-1,2-dithiol in the pres- 10). It was previously reported that the relative position between
ence of SnCl4 followed by subsequent reduction of the carbonyl the methoxy group and the amide side chain of melatonin is
Scheme 1 Synthesis of 2,3-dihydro-1H-indene derivatives. Reagents and conditions: (a) NaOH, EtOH, water, reflux; (b) dioxane, dime-
thylbenzene, reflux; SOCl2, EtOH; (c) ethane-1,2-dithiol, SnCl4, DCM; (d) LiAlH4, THF; (e) MsCl, triethylamine, DCM; isoindoline-1,3-dione,
K2CO3, CH3CN, reflux; (f) 85% hydrazine hydrate, EtOH, reflux; (g) anhydride, triethylamine, DCM; (h) AgNO3, EtOH; (i) aldehyde, MeONa, MeOH.
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Table 1 Agonistic activity of compound 2 and 10–20 on human MT1 and MT2 receptors expressed in CHO cellsa
EC50 MT1
(nM)
Emax (%)
MT1
EC50 MT2
(nM)
Emax (%)
MT2
EC50 MT1
(nM)
Emax (%)
MT1
EC50 MT2
(nM)
Emax (%)
MT2
MT1/MT2
MT1/MT2
Ramelteon
10a
11a
12a
13a
14a
15a
16a
17a
0.32
6730
338
NAb
NA
NA
NA
NA
NA
100
52
68
—
—
—
—
—
—
—
65
—
0.81
97.3
40.6
20
NA
73
92.7
222
43.9
NA
5.08
18.6
100
88
52
46
—
25
32
40
43
—
0.4
69
8
>5000
—
>1300
>1000
>450
>2200
—
2
0.36
23 200
3474
NA
NA
NA
NA
NA
NA
NA
102
40
61
—
—
—
—
—
—
—
0.97
8.97
342
NA
NA
NA
NA
NA
NA
NA
101
63
47
—
—
—
—
—
—
—
0.37
2586
10
—
—
—
—
—
—
10b
11b
12b
13b
14b
15b
16b
17b
18b
18a
19a
20a
NA
23.95
NA
—
71
61
4.7
>5300
a
Test compound potency was expressed as EC50 (nM), while the ligand selectivity towards the two receptor subtypes was expressed as the MT1/MT2
EC50 ratio. Data reported in the table were means of three or more experiments run at eight different concentrations in triplicates. b NA ¼ no agonist
effect detected at 100 mM.
essential for high receptor affinity and intrinsic activity.46 investigation opens up the possibility of further exploring MT2-
Remarkable MT2 selectivity was achieved by introduction specic agonists, which might expand our knowledge about
phenyl group to 2-position of indanone core. Compound 12a MT2 receptor in the near future.
showed good MT2 agonist potency and wonderful MT2 selec-
tivity (EC50 (MT2) ¼ 20 nM, MT1/MT2 > 5000). Replacement of
Acknowledgements
the benzene ring with unsubstituted furan ring had little
inuence to the MT2 agonistic activity and selectivity (12a vs.
17a). Substituted aromatic groups exhibited a lower potency
which was probably due to the steric effect (12a vs. 14a–16a).
Ligands with bulkier aromatic groups lost their agonistic
activity at MT2 subtype (12a vs. 13a and 18a). On the other hand,
replacement of the propionylamido group by an acetamido
group caused a signicant loss of agonistic activity for MT1 and
MT2 receptors (for example, 11a vs. 11b and 12a vs. 12b). In
addition, aliphatic substitution also led to the increase of the
MT2 agonistic activity (19a and 20a). It's worth mentioning that
the isopropyl substituted enone 19a displayed the best agonistic
activity at both subtypes and slight preference for MT2. Taken
together, these data suggested that the introduction of
substituent group to 2-position of indanone core may have an
inuence on the spatial arrangement of the amide side chain.
Surprisingly the dithiane analog with nanomolar to sub-
nanomolar agonist activity showed very high selectivity (MT1/
MT2 ¼ 2586) in its acetamido form 11b. All these effective indan
derivatives behaved as partial agonists, compounds 10b, 12a,
17a, 20a exhibited powerful MT2 agonistic activity (EC50 < 50
nM) as well as excellent MT2 selectivity (more than 2200-fold).
This work was supported by the State Key Laboratory of Drug
Research (no. SIMM1203KF-10), the grants of The National
Natural Science Foundation of China (no. 81172936 and no.
21102046), and grants of The Fundamental Research Funds for
the Central Universities.
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