Design, synthesis, and melatoninergic activity of new azido- and isothiocyanato-substituted indoles

Article abstract of DOI:10.1021/jm7010723

To develop irreversibly binding ligands for the melatonin receptor(s) as tools for tracing the primary melatonin binding site, we report on the design and synthesis of new melatoninergic azido- and isothiocyanato-substituted indoles. All active compounds were partial agonists or antagonists in the Xenopus melanophore assay, the most potent being the 5-OMe C3-substituted azido 45 and isothiocyanato 46 analogues.

Full text of DOI:10.1021/jm7010723

6436
J. Med. Chem. 2007, 50, 6436–6440
Brief Articles
Design, Synthesis, and Melatoninergic Activity of New Azido- and Isothiocyanato-Substituted
Indoles
Andrew Tsotinis,*,† Pandelis A. Afroudakis,† Kathryn Davidson,‡ Anjali Prashar,‡ and David Sugden‡
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, UniVersity of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and
DiVision of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Guy’s Campus,
London Bridge, London SE1 1UL, U.K.
ReceiVed August 30, 2007
To develop irreversibly binding ligands for the melatonin receptor(s) as tools for tracing the primary melatonin
binding site, we report on the design and synthesis of new melatoninergic azido- and isothiocyanato-substituted
indoles. All active compounds were partial agonists or antagonists in the Xenopus melanophore assay, the
most potent being the 5-OMe C3-substituted azido 45 and isothiocyanato 46 analogues.
Introduction
Melatonin (N-acetyl 5-methoxytryptamine, Figure 1) is the
principal hormone of the vertebrate pineal gland and is secreted
mainly during darkness. It is well recognized that it regulates
seasonal breeding in photoperiodic species and can entrain
circadian rhythms in mammals including man.1 Melatonin has
a hypnotic action in animals and humans,2 and ramelteon, a
Figure 1. Structures of melatonin and luzindole.
potent melatonin MT1a and MT2 receptor agonist, has recently
Scheme 1. Synthesis of the N1-Substituted Analoguesa
been granted approval for the treatment of insomnia associated
with sleep onset in the U.S.3 Melatonin has also been reported
to have antioxidant4 and antiproliferative activity.5
A number of these effects are mediated through a family of
high-affinity G-protein-coupled cell-membrane receptors MT1,
MT2, and Mel1c,6a–c which are particularly abundant in tissues
that are known to respond to melatonin (e.g., the body’s
biological clock in the suprachiasmatic nuclei of the hypothala-
mus and the retina). Melatonin receptors have been subjected
to a number of modeling studies based on the amino acid
a Reagents and conditions: (a) 1,3-dibromopropane, KOH, DMF, room
temp; (b) NaN3, DMF, 45 °C; (c) CS2, Ph3P, THF, room temp.
sequence and pharmacophore models, and a number of active
conformations have been proposed.7a–e
During the past decade, we sought to understand how
melatonininteractswithitsreceptors.Anumberofstructure-affinity
Scheme 2. Synthesis of the C2-Substituted Analoguesa
relationships have been identified, and recently we have reported
a variety of synthetic molecular probes for the melatonin binding
site.8,9a–c
In our ongoing effort to probe the stereoelectronic require-
ments for optimal activity, we report herein on a series of N1
(5–8, Scheme 1), C2 (23–26, Scheme 2), and C3 (30, 31,
Scheme 3; 39, 40 Scheme 4; and 45, 46 Scheme 5) suitably
substituted indoles as potential irreversibly binding ligands to
* To whom correspondence should be addressed. Phone: +30 210
7274812. Fax: +30 210 7274811. E-mail: tsotinis@pharm.uoa.gr.
†
University of Athens.
a Reagents and conditions: (a) SOCl2, EtOH, 70 °C; (b) LiAlH4, THF,
room temp; (c) MnO2, CH2Cl2, 35 °C; (d) Ph3PdCHCO2C2H5, benzene,
65 °C; (e) LiAlH4, THF, room temp; (f) PBr3, Et2O, 25 °C; (g) NaN3, DMF,
45 °C; (h) CS2, Ph3P, THF, room temp. The synthesis of the non-OMe
C3-substituted analogues 30 and 31 is shown in Scheme 3.
‡
King’s College London.
Abbreviations: MT1, melatonin receptor 1; MT2, melatonin receptor
a
2; Mel1c, melatonin receptor 1c; NMDA, N-methyl D-aspartate; PCP,
phencyclidine (1-(1-phenylcyclohexyl)piperidine); p-TsOH, p-toluenesul-
fonic acid; p-TsCl, p-toluenesulfonyl chloride; pIC50, the concentration of
analogue reducing melatonin-induced pigment aggregation by 50%; pEC50,
the concentration of analogue producing 50% of the maximum agonist
response.
the melatonin receptor(s). These agents may provide the basis,
in the future, for tools for tracing the primary melatonin binding
site. The design of these probes was based on the attachment
10.1021/jm7010723 CCC: $37.00
2007 American Chemical Society
Published on Web 11/08/2007

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6437
to study a number of receptors including those for PCP,17
muscarine,18 catecholamines,19,20 serotonin,21 cannabinoids,22
and retinal23 and has provided useful information on their
distribution and molecular weights or amino acid residues at or
near the active site. The only drawback of this method is the
generation of nitrenes after photoirradiation, which could
undergo intramolecular rearrangement to the respective imine.24
The situation being so, the affinity of the azido compound for
the receptor should be high enough to allow for a fast reaction
with the active site.22
The methoxy group and the ethylamide side chain of
melatonin are critical for high receptor affinity. Previous studies
have shown that changing the side chain of melatonin from C3
to N1 resulted in mainly agonist analogues, with highest affinity
when the methoxy group was shifted from C5 to C6 to maintain
the optimum spacing of functional groups.25 Moving the amido
side chain to the C2 indole position was shown to lead to partial
agonist molecules when the methoxy was shifted to C4 to again
maintain optimum spacing but gave antagonists when methoxy
was retained at C5, though with dramatically reduced affinity.26
In the present study, the pharmacophoric side chain has been
transposed from N1 to C2 to C3, and an azido or isothiocyanato
group was incorporated as a first step to developing covelent
probes that may be useful new tools for studying the receptors.
Scheme 3. Synthesis of the Non-OMe, C3-Substituted
Analoguesa
a Reagents and conditions: (a) LiAlH4, Et2O, reflux; (b) p-TsCl, pyridine,
4 °C; (c) NaN3, DMF, 45 °C; (d) CS2, Ph3P, THF, room temp.
Scheme 4. Synthesis of the C5-OMe, C3-Substituted Analogues
39 and 40a
Chemistry
The synthetic pathway followed for the preparation of
analogues 5–8 is depicted in Scheme 1. Thus, commercially
available indole (1) and 5-methoxyindole (2) were reacted with
1,3-dibromopropane in the presence of KOH in DMF to give
the N1-alkylated indolic derivatives 3 and 4,27 respectively.
These were in turn treated with an aqueous solution of sodium
azide in DMF to afford azides 5 and 6. Isothiocyanates 7 and
8 were obtained by reacting the latter with a mixture of carbon
disulfide and triphenylphosphine in THF.
a Reagents and conditions: (a) HSCH2CH2SH, BF3.OEt2, CH2Cl2, room
temp; (b) LiAlH4, THF, room temp; (c) 3,4-dihydro-2H-pyran, p-TsOH,
THF, 50 °C; (d) pyridine, CrO3, CH2Cl2, room temp; (e) concentrated HCl,
THF, 50 °C; (f) p-TsCl, pyridine, 4 °C; (g) NaN3, DMF, 45 °C; (h) CS2,
Ph3P, THF, room temp.
The synthesis of the C2-substituted indolic derivatives 23–26
(Scheme 2) was effected by esterification of 2-indolecarboxylic
acid (9) and its 5-methoxy congener 10 with thionyl chloride
and ethanol, followed by reduction of esters 1128 and 1226 with
LiAlH4 in THF to the respective alcohols 1329 and 14.26 These
compounds were then oxidized to the carboxaldehydes 1530 and
16,26 which were then converted to 1731 and 18 via a Wittig
reaction. Simultaneous reduction of the double bond and the
ester groups led to alcohols 1932 and 20, which were brominated
with PBr3 in ether to give the bromides 21 and 22. These were
treated with sodium azide in DMF, and the resulting azides 23
and 24 were reacted with CS2 and triphenylphosphine in THF
to give the isothiocyanates 25 and 26.
Scheme 5. Synthesis of the C5-OMe, C3-Substituted Analogues
45 and 46a
a Reagents and conditions: (a) (i) aqueous KOH, 100 °C, (ii) HCl
(10 N), 0 °C; (b) LiAlH4, THF, room temp; (c) p-TsCl, pyridine, 4 °C;
(d) NaN3, DMF, 45 °C; (e) CS2, Ph3P, THF, room temp.
Commercially available 3-indolepropanoic acid (27) was
reduced with LiAlH4 in diethyl ether to the alcohol 28,33 which
was tosylated with tosyl chloride in the presence of pyridine to
give 29.34 Treatment of 29 with an aqueous solution of sodium
azide in DMF gave 30, which was then reacted with carbon
disulfide and triphenylphosphine in THF to give the isothio-
cyanate 31. However, this route proved to be unsuccessful for
preparing the analogous ligands 39 and 40, and the alternative
route shown in Scheme 4 was used to obtain these systems.
The keto group of diethyl 1,3-acetonedicarboxylate (32) was
protected with 1,2-ethanedithiol in the presence of a catalytic
amount of boron trifluoride-diethyl etherate to give the 1,3-
dithiolano derivative 33,35 which was reduced with LiAlH4 in
THF to the diol 34.35 Monoprotection of the latter with
dihydropyran in the presence of p-TsOH led to the formation
of alcohol 35,36 which was oxidized under Sarett conditions to
of azido and isothiocyanato groups to the ω-position of the N1-,
C2-, and C3-alkyl side chains of the new indolic analogues.
The isothiocyanate group was chosen because it is inert in water
but capable of nucleophilic reactions with amino, imidazoyl,
and sulfhydryl functionalities on biological macromolecules
under physiological conditions.10 Moreover, isothiocyanate-
containing probes have been extensively used as tools for the
study and characterization of various receptors including
benzodiazepine,11 NMDA,12 σ,13 opioid,14,15 and cannabinoid
receptors.16 On the other hand, the azido group was introduced
in the skeletons of 5, 6, 23, 24, 30, 39, and 45, since it is known
to serve as a photoaffinity label, covalently attached to reactive
residues at or in the vicinity of the binding site, after equilibra-
tion and photoirradiation. Photoaffinity labeling has been used

6438 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Brief Articles
Table 1. Melatoninergic Activity of Compounds 5, 7, 23, 25, 30, and
31 in the Xenopus laeVis Melanophore Assaya
Table 2. Melatoninergic Activity of Compounds 6, 8, 24, 26 39, and 40
in the Xenopus laeVis Melanophore Assaya
compd
R5
agonist pEC50
antagonist pIC50
compd
R5
agonist pEC50
antagonist pIC50
melatonin
luzindole
5
7
23
25
30
31
10.07
NA
NA
PA (28%)
NA
PA (38%)
NA
PA (31%)
NA
melatonin
luzindole
6
8
24
26
39
40
10.07
NA
NA
NA
NA
PA (41%)
NA
NA
NA
5.61 ( 0.08
4.82 ( 0.01
4.04 ( 0.01
4.72 ( 0.01
4.35 ( 0.01
4.79 ( 0.02
3.92 ( 0.01
5.61 ( 0.08
4.81 ( 0.01
4.91 ( 0.01
4.15 ( 0.03
4.47 ( 0.01
5.03 ( 0.02
4.49 ( 0.02
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
a Agonist and antagonist data are the mean of triplicate experiments (
SEM. NA ) no agonist effect detected at 100 µM. PA ) partial agonist at
100 µM. Number in parentheses indicates maximal agonist action as a
percentage of that seen with 1 nM melatonin.
a Agonist and antagonist data are the mean of triplicate experiments (
SEM. NA ) no agonist effect detected at 100 µM. PA ) partial agonist at
100 µM. Number in parentheses indicates maximal agonist action as a
percentage of that seen with 1 nM melatonin.
Table 3. Melatoninergic Activity of Compounds 45 and 46 in the
Xenopus laeVis Melanophore Assaya
the aldehyde 36.36 Treatment of 36 with an acidic solution of
p-methoxyphenylhydrazine hydrochloride in THF led to the
Fischer indole product 37,37 which was first tosylated and then
converted to the desired azide 39. Isothiocyanate 40 was
obtained by reacting 39 with carbon disulfide and triphenylphos-
phine in THF.
compd
R5
agonist pEC50
antagonist pIC50
melatonin
luzindole
45
10.07
NA
NA
NA
5.61 ( 0.08
5.09 ( 0.03
5.47 ( 0.11
OCH3
OCH3
46
NA
Since it had previously been shown that the number of
methylene units between the aromatic ring and the acetamido
group was critical,9b we prepared 45 and 46 with two methylene
groups to compare with 39 and 40, which bear a 3-CH2 spacer
in their side chain. Thus, 5-methoxy-1H-3-indolacetonitrile (41)
was hydrolyzed to the acid 42,38 which was then reduced with
LiAlH4 in THF to the alcohol 43.39 This alcohol was then
converted to the chloride 44 by treatment with p-TsCl in pyridine
and the chloride converted to the azide 45 by heating with
sodium azide in aqueous DMF. Reaction of 45 with CS2 and
triphenylphosphine in THF gave the desired isothiocyanate 46.
a Agonist and antagonist data are the mean of triplicate experiments (
SEM. NA ) no agonist effect detected at 100 µM.
series, 31 (100 µM). Interestingly, the most active analogue of
this series, the azido compound 39 (pIC50 ) 5.03), is almost
equipotent to luzindole (Figure 1), a commonly used melatonin
receptor antagonist (pIC50 ) 5.61), suggesting that a modest
improvement in affinity may result in a useful melatonin receptor
probe.
Analogues 7, 25, 26, and 31 showed some agonist action,
albeit at the very highest concentration tested (100 µM) and
less than maximal activity (28–41%). This is surprising given
that these compounds lack the C5 methoxy often considered
necessary for functional agonist activity and lack any ability to
form hydrogen bonds at their ω-substituent. Furthermore, this
partial agonist action was apparent irrespective of the position
of the melatonin side chain (N1, C2, C3). Because all four were
isothiocyanate derivatives, substituted at different positions on
the indole ring, and because isothiocyanate can undergo
nucleophilic reactions with biological macromolecules under
physiological conditions, a nonspecific interaction with mel-
anophore proteins at the high concentration used must be
considered. Such an interaction may have altered intracellular
pigment position or cell morphology, giving the appearance of
receptor-mediated aggregation rather than a genuine receptor-
activated translocation of pigment.
In contrast to the three-methylene spacer analogue 40 (pIC50
) 4.49), the two-methylene congener 46 exhibits a noteworthy
improvement in antagonistic activity (pIC50 ) 5.47) (Table 3).
The shorter spacer of 46 may occupy the pocket, while the
methoxy group at C5 interacts with His211, while the longer
spacer of 40 may make hydrogen bonding of the C5 methoxy
unfavorable even if the longer side chain can be accommodated.
Radioligand binding studies on melatonin receptors and com-
putational assessment may allow this idea to be evaluated.
Results and Discussion
It is apparent from the data presented in Tables 1 and 2 that
with the exception of the isothiocyanate 7, which exhibited a
small partial agonist activity (28% of maximal) only at the
highest concentration tested (100 µM), the new N1-substituted
analogues 5, 6, and 8 are antagonists in the melanophore assay.
This is not unexpected for 5 and 7 because the loss of the critical
C5 methoxy group is known to favor an antagonist profile.
Evidence from site-directed mutagenesis and structure–activity
studies suggests that the C5 methoxy forms a hydrogen bond
with His211 in the putative transmembrane domain 5 of the
receptor.9b,40a,b Though 6 and 8 have a C5 methoxy, they are
not likely to be well accommodated in the receptor binding
site because of the unfavorable relative positions of the alkyl
side chain on N1 and the C5 methoxy group and because of
the lack of an acetamide group.
Similar behavior was also noticed in the case of the
C2-substituted analogues 23–26 (Tables 1 and 2) with weak
antagonist activity apparent, though again a small (∼40% of
maximal) partial agonist action was observed with 100 µM 25
and 26. Moving the side chain of melatonin from C3 to C2
was previously shown to lead to compounds with MT1
antagonist and partial agonist properties.26 An earlier study
reported that the C2 analogue of melatonin in which the methoxy
group was positioned at C526 exhibited a low binding affinity
(pKi ) 4.79), quite similar to the antagonist potency of 26.
For the analogues with the side chain positioned at C3,
potency remained relatively weak probably because the spacing
between the C5 methoxy and the C3 side chain, which had a
three-methylene spacer, was not optimal. Compounds 30, 39,
and 40 antagonized melatonin’s action, though a small (31%)
partial agonist response was seen with one compound in the
Conclusion
From the results presented, it becomes evident that one of
the main factors influencing antagonist potency is the location
of the side chain rather than the nature of its ω-substituent. The
information gained in the present work can be used to develop
congeners of the azido compounds as photoactivity labels and
of the isothiocyanato compounds as electrophilic probes, in order
to produce adducts covalently linked to key amino acid residues

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6439
12, 4222–4239. (e) Rivara, S.; Lorenzi, S.; Mor, M.; Plazzi, P. V.;
Spadoni, G. Analysis of structure-activity relationships for MT2
selective antagonists by melatonin MT1 and MT2 receptor models.
J. Med. Chem. 2005, 48, 4049–4060.
of the melatonin receptor subtypes. This will reveal important
stereoelectronic characteristics of the hormone’s receptor and
should lead to the development of high-affinity selective ligands.
(8) Faust, R.; Garratt, P. J.; Jones, R.; Yeh, L.-K.; Tsotinis, A. Mapping
the melatonin receptor. 6. Melatonin agonists and antagonists derived
from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroindolo[2,1-a]isoquinolines
and 6,7-dihydro-5H-benzo[c]azepino [2,1-a]indoles. J. Med. Chem.
2000, 43, 1050–1061.
(9) (a) Tsotinis, A.; Vlachou, M.; Papahatjis, D. P.; Calogeropoulou, T.;
Nikas, S. P. Mapping the melatonin receptor. 7. Subtype selective
ligands based on ꢀ-substituted N-acyl-5-methoxytryptamines and beta-
substituted N-acyl-5-methoxy-1-methyltryptamines. J. Med. Chem.
2006, 49, 3509–3519. (b) Garratt, P. J.; Travard, S.; Vonhoff, S.;
Tsotinis, A.; Sugden, D. Mapping the melatonin receptor. 4. Com-
parison of the binding affinities of a series of substituted phenylalky-
lamides. J. Med. Chem. 1996, 39, 1797–1805. (c) Garratt, P. J.;
Tsotinis, A. Synthesis of compounds as melatonin agonists and
antagonists. Mini ReV. Med. Chem. 2007, 7, 1075–1088.
(10) Assony, S. J. In Organic Sulfur Compounds; Kharasch, N., Ed.;
Pergamon Press: New York, 1961; p 326.
(11) Allen, M. S.; Hagen, T. J.; Trudell, M. L.; Codding, P. W.; Skolnick,
P. Synthesis of novel 3-substituted ꢀ-carbolines as benzodiazepine
receptor ligands: probing the benzodiazepine receptor pharmacophore.
J. Med. Chem. 1988, 31, 1854–1861.
(12) Linders, J. T.; Monn, J. A.; Mattson, M. V.; George, C.; Jacobson,
A. E. Synthesis and binding properties of MK-801 isothiocyanates;
(+)-3-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-
hepten-5,10-imine hydrochloride: a new, potent and selective elec-
trophilic affinity ligand for the NMDA receptor-coupled phencyclidine
binding site. J. Med. Chem. 1993, 36, 2499–2507.
Experimental Section
General Procedure 1 for the Preparation of Azides 5, 6,
23, 24, 30, 39, and 45. A solution of sodium azide (0.42 g, 7.63
mmol) in H2O (2 mL) was added dropwise to a stirred solution of
the appropriate bromide or chloride (for the synthesis of 45) (3.36
mmol) in DMF (6 mL) at room temperature. The resulting mixture
was then heated to 45 °C and stirred at this temperature for 3 h.
Upon completion of the reaction, the mixture was poured onto
crushed ice and extracted with AcOEt. The organic phase was
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue obtained was purified by flash column chromatography
to give the title azides as pale-yellow oils.
General Procedure 2 for the Preparation of Isothiocyanates
7, 8, 25, 26, 31, 40, and 46. Carbon disulfide (4.36 g, 3.4 mL, 57.4
mmol) and triphenylphosphine (0.89 g, 3.06 mmol) were sequen-
tially added to a solution of the above azides (2.05 mmol) in THF
(15 mL). The suspension formed was stirred for 20 h at room
temperature, and upon completion of the reaction, the solvent was
removed in vacuo. The residue obtained was purified by flash
column chromatography to give the desired isothiocyanates as
yellowish oils.
Acknowledgment. The University of Athens group thanks
the EPEAEK II program Pythagoras IIsSupport of Universities
Research Groups (Grant KA 70/3/7993) for financial support.
The King’s College London group was supported by the
Wellcome Trust (grant GR065816).
(13) Adams, J. T.; Teal, P. M.; Sonders, A. S.; Tester, B.; Esherick, J. S.
Synthesis and characterization of an affinity label for brain receptors
to psychotomimetic benzomorphans: differentiation of σ-type and
phencyclidine receptors. Eur. J. Pharmacol. 1987, 142, 61–71.
(14) Rice, K. C.; Jacobson, A. E.; Burke, T. R., Jr.; Bajwa, B. S.; Streaty,
R. A. Irreversible ligands with high selectivity toward δ- and µ-opiate
receptors. Science 1983, 220, 314–316.
(15) Portoghese, P. S.; Sultana, M.; Takemori, A. E. Naltrindole 5′-
isothiocyanate: a non-equilibrium, highly selective δ-opioid receptor
antagonist. J. Med. Chem. 1990, 33, 1547–1548.
(16) Guo, Y.; Abadji, V.; Morse, K. L.; Fournier, D. J.; Li, X. (-)-11-
Hydroxy-7′-isothiocyanato-1′,1′-dimethylheptyl-∆8-THC: a novel, high-
affinity irreversible probe for the cannabinoid receptor in the brain.
J. Med. Chem. 1994, 37, 3867–3870.
Supporting Information Available: Experimental details on the
synthesis of the compounds in this paper, spectral data for all
compounds, elemental analysis data for key target compounds, and
pharmacological assay. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Haring, R.; Kloog, Y.; Sokolovsky, M. Identification of polypeptides
of the phencyclidine receptor of rat hippocampus by photoaffinity
labeling with [3H]azidophencyclidine. Biochemistry 1986, 25, 612–
620.
(18) Sokolovsky, M. Photoaffinity labeling of muscarinic receptors. Phar-
macol. Ther. 1987, 32, 285–292.
(19) Leeb-Lundberg, L. M.; Cotecchia, S.; DeBlasi, A.; Caron, M. G.;
Lefkowitz, R. J. Regulation of adrenergic receptor function by
phosphorylation. I. Agonist-promoted desensitization and phospho-
rylation of alpha 1-adrenergic receptors coupled to inositol phospho-
lipid metabolism in DDT1 MF-2 smooth muscle cells. J. Biol. Chem.
1987, 262, 3098–3105.
(20) Kanety, H.; Fuchs, S. Immuno-photoaffinity labeling of the D2-
dopamine receptor. Biochem. Biophys. Res. Commun. 1988, 155, 930–
936.
(21) Raymond, J. R.; Fargin, A.; Lohse, J. M.; Regan, J. W.; Senogles,
S. E. Identification of the ligand-binding subunit of the human
5-hydroxytryptamine 1A receptor with N-(p-azido-m-[125I]iodophen-
ethyl)spiperone, a high affinity radioiodinated photoaffinity probe. Mol.
Pharmacol. 1989, 36, 15–21.
(22) Charalambous, A.; Yan, G.; Houston, D. B.; Howlett, A. C.; Compton,
D. R. 5′-Azido-∆8-THC: a novel photoaffinity label for the cannabinoid
receptor. J. Med. Chem. 1992, 35, 3076–3079.
(23) Nakayama, T. A.; Khorana, H. G. Orientation of retinal in bovine
rhodopsin determined by cross-linking using a photoactivatable
analogue of 11-cis-retinal. J. Biol. Chem. 1990, 265, 15762–15769.
(24) Kyba, E. P. Alkyl Azides and Nitrenes. In Azides and Nitrenes;
Scriven, E. F. V., Ed.; Academic Press, Inc.: Orlando, FL, 1971; pp
23–28.
(25) Tarzia, G.; Diamantini, G.; Di Giacomo, B.; Spadoni, G.; Esposti, D.
1-(2-Alkanamidoethyl)-6-methoxyindole derivatives: a new class of
potent indole melatonin analogues. J. Med. Chem. 1997, 40, 2003–
2010.
References
(1) Bartness, T. J.; Powers, J. B.; Hastings, M. H.; Bittman, E. L.;
Goldman, B. D. The timed infusion paradigm for melatonin delivery:
what has it taught us about the melatonin signal, its reception, and
the photoperiodic control of seasonal responses. J. Pineal Res. 1993,
15, 161–190.
(2) Garfinkel, D.; Laudon, M.; Nof, D.; Zisapel, N. Improvement of sleep
quality in elderly people by controlled-release melatonin. Lancet 1995,
346, 541–544.
(3) Wurtman, R. Ramelteon: a novel treatment for the treatment of
insomnia. Expert ReV. Neurother. 2006, 6, 957–964.
(4) Iakovou, K.; Varvaresou, A.; Kourounakis, A. P.; Stead, K.; Sugden,
D. Design, synthesis and biological evaluation of novel ꢀ-substituted
indol-3-yl ethylamido melatoninergic analogues. J. Pharm. Pharmacol.
2002, 54, 147–156.
(5) Molis, T. M.; Spriggs, L. L.; Jupiter, Y.; Hill, S. M. Melatonin
modulation of estrogen-regulated proteins, growth factors, and proto-
oncogenes in human breast cancer. J. Pineal Res. 1995, 18, 93–103.
(6) (a) Reppert, S. M.; Weaver, D. R.; Ebisawa, T. Cloning and
characterization of a mammalian melatonin receptor that mediates
reproductive and circadian responses. Neuron 1994, 13, 1177–1185.
(b) Reppert, S. M.; Godson, C.; Mahle, C. D.; Weaver, D. R.;
Slaugenhaupt, S. A. Molecular characterisation of a second melatonin
receptor expressed in human retina and brain: the Mel1b melatonin
receptor. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 8734–8738. (c)
Ebisawa, T.; Karne, S.; Lerner, M. R.; Reppert, S. M. Expression
cloning of a high-affinity melatonin receptor from Xenopus dermal
melanophores. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 6133–6137.
(7) (a) Mor, M.; Plazzi, P. V.; Spadoni, G.; Tarzia, G. Melatonin. Curr.
Med. Chem. 1999, 6, 501–518. (b) Zlotos, D. P. Recent advances in
melatonin receptor ligands. Arch. Pharm. (Weinheim, Ger.) 2005, 338,
229–247. (c) Voronkov, A. E.; Ivanov, A. A.; Baskin, I. I.; Palyulin,
V. A.; Zefirov, N. S. Molecular modeling study of the mechanism of
ligand binding to human melatonin receptors. Dokl. Biochem. Biophys.
2005, 403, 284–288. (d) Uchikawa, O.; Fukatsu, K.; Tokunoh, R.;
Kawada, M.; Matsumoto, K. Synthesis of a novel series of tricyclic
indan derivatives as melatonin receptor agonists. J. Med. Chem. 2002,
(26) Spadoni, G.; Balsamini, C.; Bedini, A.; Diamantini, G.; Di Giacomo,
B. 2-[N-Acylamino(C1-C3)alkyl]indoles as MT1 melatonin receptor
partial agonists, antagonists, and putative inverse agonists. J. Med.
Chem. 1998, 41, 3624–3634.

6440 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25
Brief Articles
(27) Dehaen, W.; Hassner, A. Cycloadditions. Annulation of heterocycles
via intramolecular nitrile oxide-heterocycle cycloaddition reaction.
J. Org. Chem. 1991, 56, 896–900.
(28) Wadia, M. S.; Mali, R. S.; Tilve, S. G.; Yadav, V. J. Facile syntheses of
ethyl 2-alkylindole-3-carboxylates: reinvestigation of an earlier synthesis
of ethyl 3-methylindole-2-carboxylates. Synthesis 1987, 4, 401–404.
(29) Mahanty, J. S.; De, M.; Das, P.; Kundu, N. G. Palladium-catalyzed
heteroannulation with acetylenic carbinols as synthons—synthesis of
quinolines and 2,3-dihydro-4(1H)-quinolones. Tetrahedron 1997, 53,
13397–13418.
(30) Pérez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Gonzáles-Pérez,
P.; Pérez-Castells, J. Synthesis of enynoindoles via vinyl and ethynyl
indoles. Synthesis 2002, 13, 1810–1812.
(31) Bit, R. A.; Davis, P. D.; Hill, C. H.; Keech, E.; Vesey, D. R. A.
Dieckmann/ring expansion approach to tetrahydropyrido- and tetrahy-
droazepino-[1,2-a]indoles. Tetrahedron 1991, 47, 4645–4664.
(32) Smith, A. B.; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Organometallic reagents in synthesis: a new protocol for construction
of the indole nucleus. Tetrahedron 1986, 42, 2957–2969.
(33) Benghiat, E.; Crooks, P. A. Multisubstrate adducts as potential
inhibitors of S-adenosylmethionine dependent methylases: inhibition
of indole N-methyltransferase by (5′-deoxyadenosyl)[3-(3-indolyl)prop-
1-yl]methylsulfonium and (5′-deoxyadenosyl)[4-(3-indolyl)but-1-yl]-
methylsulfonium salts. J. Med. Chem. 1983, 26, 1470–1477.
(34) Beck, L.; Mascal, M.; Moody, C. J.; Coates, W. J. Synthesis of
3,4-bridged indoles by photocyclisation reactions. Part 2. Photo-
cyclisation of halogenoacetyl tryptophol derivatives and R-chloro
indol-3-ylalkanoate esters. J. Chem. Soc., Perkin Trans. 1 1992, 813–
821.
(35) Berglund, R. A.; Fuchs, P. L. Synthesis of fluorinated dienylic
stannanes via the Wadsworth-Emmons reaction. Synth. Commun.
1989, 19, 1965–1980.
(36) Zepeda, L. G.; Cervantes, H.; Morales-Rios, M. S.; Joseph-Nathan,
P. Synthesis of 3,3-dimethylenedithio-5-oxyaldehydes. Synth. Commun.
1991, 21, 1369–1381.
(37) Zepeda, L. G.; Morales-Rios, M. S.; Joseph-Nathan, P. Fischer indole
synthesis of (ꢀ-oxo)indol-3-yl ketones using protected 1,3-dicarbonyl
compounds. Synth. Commun. 1992, 22, 3243–3256.
(38) Morales-Rios, M. S.; Santos-Sánchez, N. F.; Suárez-Castillo, O. R.;
Joseph-Nathan, P. Aromatic bromination versus oxidation of indolyl-
malonates by bromine. J. Org. Chem. 2003, 68, 305–311.
(39) Chou, S.-Y. A novel substitution reaction of tetrahydropyrano[3,4-
b]indole derivative—chain extension and structural correlation. Het-
erocycles 2003, 60, 1095–1110.
(40) (a) Davies, D. J.; Faust, R.; Garratt, P. J.; Marivingt-Mounir, C.;
Davidson, K. Binding affinity and biological activity of oxygen and
sulfur isosteres at melatonin receptors as a function of their hydrogen
bonding capacity. Bioorg. Chem. 2004, 32, 1–12. (b) Barrett, P.;
Conway, S.; Jockers, R.; Strosberg, A. D.; Guardiola-Lemaitre, B.
Cloning and functional analysis of a polymorphic variant of the ovine
Mel 1a melatonin receptor. Biochem. Biophys. Acta 1997, 1356,
299–307.
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