Synthesis of N1-phenethyl substituted indole derivatives as new melatoninergic agonists and antagonists.

Article abstract of DOI:10.1248/cpb.50.31

The potency of new indolic N1-phenethyl substituted melatoninergic ligands with and without methyl groups in the alpha and beta position of the alkanamidoethyl side chain was examined using the pigment aggregation response in a clonal line of Xenopus laev

Full text of DOI:10.1248/cpb.50.31

January 2002
Chem. Pharm. Bull. 50(1) 31—39 (2002)
31
Synthesis of N1-Phenethyl Substituted Indole Derivatives as New
Melatoninergic Agonists and Antagonists
Andrew TSOTINIS, ,a Margarita VLACHOU,a Andreas ELEUTHERIADES,a Effie PRINEA,a Darren EBREO,b
*
b
Muy-Teck THE,b and David SUGDEN
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens,a Panepistimiopolis-Zografou, 157 71
Athens, Greece and Endocrinology & Reproduction Research Group, GKT School of Biomedical Sciences, New Hunts
House, King’s College London, Guy’s Campus,b London Bridge, London SE1 1UL, U.K.
Received June 18, 2001; accepted September 17, 2001
The potency of new indolic N1-phenethyl substituted melatoninergic ligands with and without methyl
groups in the a and b position of the alkanamidoethyl side chain was examined using the pigment aggregation
response in a clonal line of Xenopus laevis melanophores. The non 5-OMe substituted compounds, 8a—e, are all
weak antagonists while introduction of the 5-OMe group, 9a—e, increases both agonist and antagonist activity
except for 9c (R؍C3H7), which is only an agonist and 9e (R؍c-C4H7), which is only an antagonist. Introduction
of an a-methyl group into the 5-OMe derivatives, 14a—e, reduces the agonist potency while introduction of a b-
methyl group has only a small effect on either the agonist or antagonist potency. Double b-methyl substitution of
the 5-OMe derivatives, 20a—e, generally increases the agonist potential (20c, R؍C3H7 is the most potent agonist
of the compounds described) and decreases the antagonist potency, except for 20a (R؍CH3), which is the most
potent antagonist of this series of compounds.
Key words N1- substituted indole; synthesis; Xenopus laevis melanophore model; melatonin agonist/antagonist
Melatonin (N-acetyl-5-methoxytryptamine), Fig. 1, is a fect to agonistic activity.20,21) Conversely, the introduction of
vertebrate pineal gland hormone, which is secreted mainly at one or two methyl groups in the b position of the alkanami-
night.1) Melatonin has been shown to have a physiologi- doethyl side chain of naphthalene analogs leads to increased
cal role in regulating seasonal breeding in photoperiodic potency.22)
species2) and can entrain circadian rhythms.3) The hormone
In order to probe the constraints at the receptor site with
also increases vascular tone in the rat tail artery4) and cere- regard to the lower N1–C2 region of the indole moiety of
bral vascular bed5) and inhibits [3H]dopamine release from melatonin, we have recently reported the synthesis and bio-
rabbit retina.6) In addition, a sleep-promoting action of mela- logical activity of a number of 2-phenyltryptamines annu-
tonin has been repeatedly observed in animal and human lated on the [a] face of the pyrrole moiety by the introduc-
studies.7) Melatonin analogs are currently being examined as tion of 1, 2 or 3 methylene groups, 1—3, Fig. 2.23) In the
a therapy for treating circadian rhythm disturbances resulting Xenopus melanophore pigment aggregation model, com-
from various causes (e.g. jet-lag, shift-work, blindness) and pounds 1a—j were found to exhibit agonist activity while
the use of melatonin as a hypnotic has been advocated.8) their congeners 3a—j were antagonists. Molecules 2a—d
Molecular cloning data suggest that melatonin exerts all of were antagonists and 2e—h had agonist activity at low con-
these effects through a family of specific, high affinity, G- centrations but antagonised responses at high concentrations,
protein coupled cell membrane receptors, MT1, MT2, and Fig. 2. These findings suggest that the Xenopus melatonin re-
Mel1c,9) which have been detected in tissues known to re- ceptor can not accommodate an N-n-alkyl chain attached to a
spond to melatonin (e.g. in the retina and the suprachiasmatic phenyl ring substituent with nϾ2 (Fig. 2, compounds 3a—j)
nuclei of the hypothalamus).
in the required orientation to induce or stabilize the active re-
Our understanding of the physiological and pathophysio- ceptor conformation.
logical role(s) of melatonin in animals and man is hampered
In the present study, we have extended this work to synthe-
by the relatively small number of melatonin receptor agonists size and evaluate a number of novel N-{2-[1-(2-phenethyl)-
and antagonists available. In a series of studies during the 1H-indol-3-yl]ethyl}alkanamides 8a—e and N-{2-[5-me-
last decade we have sought to understand how melatonin thoxy-1-(2-phenethyl)-1H-indol-3-yl]ethyl}alkanamides
binds to and activates its receptor and to use the knowledge 9a—e (Chart 1). These analogs may probe the constraints at
gained to design potent receptor agonists and antagonists, the receptor site with regard to the lower N1 region of the in-
which will be useful tools for defining the full physiological
and pathophysiological role of this hormone. Thus, several
key interactions between ligand and receptor have been iden-
tified. The 5-methoxy group and amide moiety, and their rel-
ative position, are critical to high affinity.10—17) The size of
the acyl group is important for the binding of the side chain
to the receptor and in some cases (N-cyclopropanoyl and N-
cyclobutanoyl groups) it decreases the intrinsic activity of the
corresponding compounds.18,19) In naphthalene and indole
derivatives the presence of an a-methyl group in the alka-
namidoethyl side chain is reported to exert a detrimental ef-
Fig. 1
To whom correspondence should be addressed. e-mail: tsotinis@pharm.uoa.gr
© 2002 Pharmaceutical Society of Japan

32
Vol. 50, No. 1
Fig. 2. Structures of Compounds 1—323)
a NAϭNo agonist or antagonist effect detected at 100 mM.
(a) KOH, DMF; (b) LiAlH4, diethyl ether, benzene; (c) (RCO)2O or RCOCl, Et3N, dichloromethane.
Chart 1
dole moiety in a similar way to compounds 1—3 without amines 7a and b, which were not purified but were
through linking of the phenyl ring to C-2. In order to explore immediately acylated with the appropriate reagent23) to give
the possible synergistic influence on potency upon introduc- the desired N-{2-[1-(2-phenethyl)-1H-indol-3-yl]ethyl}alkan-
ing a and b-methyl substituents on the ethyl chain of systems amides 8a—e and N-{2-[5-methoxy-1-(2-phenethyl)-1H-
of types 8 and 9, we also prepared N-{2-[5-methoxy-1-(2- indol-3-yl]ethyl}alkanamides 9a—e.
phenethyl)-1H-indol-3-yl]-1-methylethyl}alkanamides 14a—
The synthesis of analogs 14a—e is shown in Chart 2. 5-
e, N-{2-[5-methoxy-1-(2-phenethyl)-1H-indol-3-yl]propyl}- Methoxyindole-3-carboxaldehyde (10) was condensed with
alkanamides 17a—e and the analogous b,bЈ-dimethyl deriva- the tosylate 5 to furnish aldehyde 11 and the sequence of the
tives 20a—e (Charts 2—4).
Henry reaction23) with nitroethane followed by reduction23)
gave the amine 13, which was acylated with the appropriate
reagent23) to give the desired N-{2-[5-methoxy-1-(2-phen-
Chemistry
Compounds 8a—e and 9a—e were prepared by the syn- ethyl)-1H-indol-3-yl]-1-methylethyl}alkanamides 14a—e.
thetic pathway depicted in Chart 1. 3-Indolylacetonitrile (4a)
The b-methyl substituted derivatives 17a—e (Chart 3)
and 5-methoxyindole-3-acetonitrile24) (4b) were separately were obtained by acylation of the amine 16, which was pre-
reacted with the tosylate 5, prepared from 2-phenylethanol pared by the reduction of the a-methyl cyano analog 15. The
and p-toluenesulfonyl chloride (TsCl),23) to give the N-alky- latter was derived from acetonitrile 6b by methylation with
lated acetonitriles 6a and b, respectively. These were reduced methyl iodide in the presence of sodium hydride and N,N-di-
with lithium aluminun hydride in the presence of diethyl methylformamide (DMF).
ether and benzene (5 : 1 v/v)25) to afford the corresponding
The preparation of the b,bЈ-dimethyl congeners 20a—e

January 2002
33
(a) K2CO3, acetonitrile; (b) CH3CH2NO2, AcONH4; (c) LiAlH4, THF; (d) (RCO)2O or RCOCl, Et3N, dichloromethane.
Chart 2
(a) NaH, CH3I, DMF; (b) LiAlH4, diethyl ether, benzene; (c) (RCO)2O or RCOCl, Et3N, dichloromethane.
Chart 3
(Chart 4) was effected by following the procedure described Results and Discussion
for the synthesis of derivatives 17a—e, with excess methyl
iodide.
The agonist and antagonist potency of the new compounds
was assessed in the Xenopus laevis melanophore model. Like
luzindole, (Fig. 1), a commonly used melatonin receptor an-

34
Vol. 50, No. 1
(a) NaH, CH3I, DMF; (b) LiAlH4, diethyl ether, benzene; (c) (RCO)2O or RCOCl, Et3N, dichloromethane.
Chart 4
tagonist (pIC50ϭ5.61), all of the non 5-OMe substituted Table 1. Agonistic and Antagonistic Activity of Compounds 8a—e and
9a—e in the Xenopus laevis Melanophore Assay
analogs, 8a—e, are antagonists in the above assay. The size
and the nature of the acyl group in the side chain does not
Compound
R5
R
Agonist pEC50 Antagonist pIC50
seem to play a significant role in their potency, the pIC50 val-
ues obtained for these molecules being similar (Table 1).
These results are in agreement with our earlier findings,
which suggest that, in contrast to agonists, antagonist po-
tency varies little with the increase in chain length of the N-
acylating group.26) A recent site-directed mutagenesis study
has provided strong molecular evidence that agonist and an-
tagonist binding sites are not identical.27)
Introduction of a methoxyl group at C-5, compounds 9a—
e, gave analogs showing varying degrees of agonist activity.
Compound 9a was a moderately potent (pIC50ϭ6.80) partial
agonist (maximum effect 33%), while 9b showed very slight
(15% at 10 mM) and 9d had no agonist action (Ͻ10% at
10 mM). The exception was 9c, which was a full agonist of
moderate potency (pIC50ϭ7.16). Compared to the analogous
tetracyclic compounds, 2e—h, the present series appears to
have less intrinsic agonist activity. Interestingly, 9c, like 2e,
are full agonists with no antagonist activity whereas 9a and b
show some agonist behavior, but are also antagonists. The in-
troduction of the methoxyl group at C-5 did not lead to the
expected decrease in the antagonistic activity of molecules
9b, d and e (Table 1). This is in contrast to the biological
data obtained on the previously reported analogous tetra-
cyclic compounds 2a—h.23)
Melatonin
Luzindole
10.07
NA
NA
NA
NA
—
5.61
4.47
4.51
4.94
4.49
4.56
5.45
5.24
NA
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
C2H5
C3H7
c-C3H5
c-C4H7
CH3
C2H5
C3H7
c-C3H5
c-C4H7
NA
NA
6.80 (33%)
Ͼ5 (15%)
7.16
Ͼ5 (5%)
NA
5.25
4.86
NAϭno agonist or antagonist effect detected at 100 mM. Number in brackets indi-
cates the degree of agonist response as a percentage of maximum. Agonist and antago-
nist data on melanophores are the mean of 3 to 6 experiments.
of the amide side chain in 14a—e eliminated the partial ago-
nist potency of analogs 9a and b as well as the full agonistic
activity of their counterpart 9c. One can envisage that a-
methyl substitution in the alkanamidoethyl chain of 14a—e
comprises an unfavorable steric parameter for recognition by
melatonin receptors,22) which surmounts the contribution to
agonistic activity exerted by the 5-OMe group and the acyl-
amido group in analogs 9a, b and c, respectively.
The introduction of a b-methyl substituent in the amide
side chain of 17a—e does influence in some cases the activa-
tion process of the receptor by molecules with agonistic ac-
tivity. Thus, in this series, analogs 17b and d behave as mod-
erately potent partial agonists (46 and 56% of maximal activ-
ity respectively) while their congener 17c exhibits essentially
full agonistic potency (86% of maximum, Table 2). These
findings seem to parallel earlier results with other indolic de-
rivatives, which demonstrated that there is a preferred orien-
The exception observed in the full agonist activity of com-
pound 9c could be attributed to a synergistic effect caused by
the presence of the 5-OMe group and the size of the acyl
group (RϭC3H7). The simultaneous incorporation of both of
these moieties to indole analogs is known to drastically en-
hance melatoninergic agonistic activity.18)
The a-methyl substituted analogs 14a—e were slightly
better antagonists than their congeners 9a—e (Table 2). Fur-
thermore, the introduction of a methyl group at the a-carbon

January 2002
35
Table 2. Agonistic and Antagonistic Activity of Compounds 14a—e and
17a—e in the Xenopus laevis Melanophore Assay
the length of the N-acylamido group. One thus must presume
that the presence of methyl substituents in the side chain of
these molecules contributes to some extent to their disposi-
tion in the receptor pocket. However, the lack of annulation
of the 2-phenethyl group on the [a] face of the pyrrole moi-
ety seems to reduce their ability to dock onto the receptor.
Continuing the attempts to define the characteristics of
melatonin required for ligand binding and receptor activa-
tion, we are currently engaged with the synthesis of new se-
ries of melatoninergic analogs.
Compound
R
Agonist pEC50
Antagonist pIC50
Melatonin
Luzindole
14a
10.07
NA
NA
NA
5.61
5.85
CH3
C2H5
14b
NA
5.47
14c
C3H7
NA
5.60
14d
14e
17a
c-C3H5
c-C4H7
CH3
NA
NA
NA
5.78
5.85
6.26
Experimental
17b
17c
17d
17e
C2H5
C3H7
c-C3H5
c-C4H7
6.35 (46%)
6.76 (86%)
6.74 (56%)
NA
4.89
Ͻ4 (19%)
5.02
Melting points were determined on a Büchi 530 apparatus and are uncor-
1
rected. H- and 13C-NMR spectra were taken in CDCl3 and recorded on a
Bruker AC200 MHz spectrometer. The spectra are reported in ppm (d) val-
ues and tetramethylsilane was used as internal standard. All the experiments
were carried out under an atmosphere of Argon. The solvents used were
dried as follows: Benzene using sodium wire, triethylamine over sodium hy-
droxide, DMF and dichloromethane over molecular sieves (4 Å) and diethyl
ether and tetrahydrofuran (THF) over calcium hydride. DC-Alufolien plates
(Kieselgel 60 F254, Schichtdicke 0.2 mm, Merck) were used for analytical
TLC and were visualized with ultraviolet light or developed with iodine or
phosphomolybdic acid. Microanalyses were carried out by the Microanalyti-
cal Section of the Institute of Organic and Pharmaceutical Chemistry, Na-
tional Hellenic Research Foundation (NHRF). 3-Indolylacetonitrile (4a), 5-
methoxyindole-3-carboxaldehyde (10) and 2-phenylethanol were purchased
from Aldrich Chemical Company (Gillingham, Dorset, U.K.).
[1-(2-Phenethyl)-1H-indol-3-yl]acetonitrile (6a) Powder potassium
hydroxide 85% (0.76 g, 13.57 mmol) was added to a chilled (0 °C) solution
of commercially available 3-indolylacetonitrile (4a) (0.91 g, 5.86 mmol) in
DMF (25 ml). After the suspension had been stirred for 5 min a solution of
the tosylate 5 (2.19 g, 7.93 mmol) in DMF (8 ml) was added dropwise and
the reaction mixture was stirred at 0 °C for 30 min and then at ambient tem-
perature for 16 h. Upon completion of the reaction (TLC control) the dark
suspension was partitioned between AcOEt and water. The organic layer was
successively washed with water and brine and then dried over Na2SO4. The
solvent was removed in vacuo to leave an oily residue, which was flash chro-
matographed eluting with cyclohexane/AcOEtϭ94 : 6 to give 1.34 g (88%)
of 6a as a viscous oil. 1H-NMR d: 2.96 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.65 (2H,
s, CH2CN), 4.18 (2H, t, NCH2, Jϭ7.3 Hz), 6.87 (1H, s, H2), 6.90—7.02 (4H,
m, Harom), 7.15—7.30 (5H, m, Harom); 13C-NMR d: 14.0 (t), 36.7 (t), 48.2 (t),
99.6 (d), 102.2 (s), 110.4 (d), 112.4 (d), 118.0 (s), 126.5 (d), 126.8 (d), 128.4
(d), 131.2 (s), 136.8 (d), 137.8 (d). Anal. Calcd for C18H16N2: C, 83.04; H,
6.19; N, 10.76. Found: C, 82.72; H, 6.24; N, 10.58.
6.12
NAϭno agonist or antagonist effect detected at 100 mM. Number in brackets indi-
cates the degree of agonist response as a percentage of maximum. Agonist and antago-
nist data on melanophores are the mean of triplicate experiments.
Table 3. Agonistic and Antagonistic Activity of Compounds 20a—e in the
Xenopus laevis Melanophore Assay
Compound
R
Agonist pEC50
Antagonist pIC50
Melatonin
Luzindole
20a
10.07
NA
NA
7.92
8.01 (92%)
NA
NA
5.61
6.74
4.61
4.39
4.69
4.79
CH3
C2H5
C3H7
c-C3H5
c-C4H7
20b
20c
20d
20e
7.02 (65%)
NAϭno agonist or antagonist effect detected at 100 mM. Number in brackets indi-
cates the degree of agonist response as a percentage of maximum. Agonist and antago-
nist data on melanophores are the mean of triplicate experiments.
tation of the 3-amidoethane side chain, which is more highly
populated when there is a methyl group at the b carbon of
the 3-amidoethyl moiety.18) The lack of agonistic activity,
particularly of analog 17e, could be ascribed to the presence
of the N-cyclobutanoyl group in its side chain, a moiety,
which is known to exert a detrimental effect to agonistic po-
tency.18,28)
[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]acetonitrile
(6b) Com-
pound 6b was obtained in the same manner as 6a in 86% yield as a beige
solid after purification by flash chromatography using cyclohexane/
AcOEtϭ94 : 6. mp 88—89 °C (petroleum ether 40—60 °C/ethyl acetate).
The situation is quite different when two methyl groups
are present at the b carbon of the 3-amidoethane side chain 1H-NMR d: 2.99 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.65 (2H, s, CH2CN), 3.82 (3H,
s, OCH3), 4.18 (2H, t, NCH2, Jϭ7.3 Hz), 6.82 (1H, s, H2), 6.88 (1H, dd, H6,
of molecules 20a—e. Again, as for a single methyl b-sub-
stituent, 17a, the acetamido analog 20a with two methyl
groups has no agonist activity, while the butyramido analogs
Jϭ2.6, 9.5 Hz), 6.94—7.04 (3H, m, Harom), 7.11—7.30 (4H, m, Harom). 13C-
NMR d: 14.0 (t), 36.5 (t), 48.0 (t), 55.6 (q), 99.7 (d), 102.2 (s), 110.4 (d),
112.5 (d), 118.1 (s), 126.5 (d), 126.7 (d), 128.5 (d), 131.2 (s), 138.0 (d),
17c and 20c both retain full agonist activity. Compound 20c
(RϭC3H7) has full agonist activity (92% of maximum) as
does its equivalent analog 17c with a single b-methyl sub-
stituent (86% of maximum). The second methyl substitution
appears to increase both agonist and antagonist activity
(Table 3).
In conclusion, the biological data presented herein for the
five series of analogs suggest that although the structural
changes made constitute relatively minor interpositions onto
the basic nucleus, the consequences are quite significant.
Specifically, methyl substitution on the a-carbon of the acyl-
amido side chain eliminates the ability to activate the mela-
tonin receptor. A single or double methyl substitution on the
b-carbon of the side-chain does not drastically impede the
access of compounds to the agonist site on the receptor, al-
154.1 (s). Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C,
78.29; H, 6.30; N, 9.35.
2-[1-(2-Phenethyl)-1H-indol-3-yl]ethylamine (7a) A solution of 6a
(0.47 g, 1.81 mmol) in benzene (2 ml) was added dropwise to a suspension
of lithium aluminum hydride (0.21 g, 5.46 mmol) in dry diethyl ether (10 ml)
at 0 °C. The mixture was then refluxed for 1.5 h and upon cooling to 0 °C it
was carefully treated with water (5 ml). The resulting suspension was filtered
through Celite and the filtrate diluted with diethyl ether. The ether layer was
washed with water and brine, dried over Na2SO4 and concentrated under re-
duced pressure to give 0.46 g (97%) of the crude amine 7a as a yellow oil,
which was used without further purification in the acylation reactions.
2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]ethylamine (7b) Amine
7b was prepared according to the procedure described above for 7a. Yield
(95%).
Preparation of the Amides 8a—e and 9a—e Triethylamine (0.07 ml,
0.48 mmol) was added to a solution of the amine 7a or b (0.36 mmol) in
dichloromethane (1 ml) at 0 °C. The mixture was stirred at this temperature
for 10 min and the appropriate acid anhydride (0.42 mmol in the case of
though varying degrees of full agonistic activity depend on compounds 8a—c and 9a—c) or acid chloride (0.45 mmol in the case of

36
Vol. 50, No. 1
compounds 8d, e and 9d, e) was then added. After the addition the mixture
was left stirring at room temperature for 30 to 60 min before water was
added. The resulting mixture was extracted with dichloromethane, washed
with water and brine and dried over Na2SO4. The solvent was removed in
vacuo to give the crude amides as viscous oils. Unless otherwise indicated
the amides were triturated with AcOEt (1 ml) to afford the title compounds
as amorphous solids.
N-{2-[1-(2-Phenethyl)-1H-indol-3-yl]ethyl}acetamide (8a): Beige solid,
47%. mp 162—164 °C. 1H-NMR d: 1.90 (3H, s, COCH3), 2.90 (2H, t,
CH2CH2NH, Jϭ6.6 Hz), 3.10 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.52 (2H, dt,
CH2CH2NH, Jϭ6.2, 6.8 Hz), 4.32 (2H, t, NCH2, Jϭ7.3 Hz), 5.43 (1H, br s,
NH), 6.73 (1H, s, H2), 7.03—7.30 (7H, m, Harom), 7.35 (1H, d, H7,
Jϭ8.0 Hz), 7.59 (1H, d, H4, Jϭ7.7 Hz). 13C-NMR d: 23.1 (q), 25.2 (t), 36.8
(t), 39.8 (t), 48.5 (t), 106.7 (s), 111.0 (d), 119.6 (d), 120.5 (d), 121.7 (d),
124.1 (d), 126.6 (d), 127.5 (s), 127.7 (d), 128.4 (d), 135.5 (s), 137.5 (s),
170.1 (s). Anal. Calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found: C,
78.32; H, 7.22; N, 9.20.
(1H, br s, NH), 6.70 (1H, s, H2), 6.88 (1H, dd, H6, Jϭ2.2, 9.0 Hz), 7.00—
7.12 (3H, m, Harom), 7.19—7.32 (4H, m, Harom). 13C-NMR d: 9.7 (q), 25.5
(t), 29.5 (t), 36.5 (t), 39.5 (t), 48.2 (t), 55.7 (q), 100.6 (d), 110.2 (d), 110.8
(s), 112.5 (d), 126.5 (d), 126.7 (d), 128.6 (d), 128.8 (s), 131.5 (s), 138.6 (d),
153.7 (s), 169.8 (s). Anal. Calcd for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99.
Found: C, 75.25; H, 7.55; N, 7.89.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]ethyl}butyramide (9c):
White solid, 31%. mp 104—106 °C. 1H-NMR d: 0.94 (3H, t, CH2CH3,
Jϭ7.7 Hz), 1.58 (2H, sextet, CH2CH2CH3, Jϭ7.5 Hz), 2.09 (2H, t, COCH2,
Jϭ7.7 Hz), 2.89 (2H, t, CH2CH2NH, Jϭ6.9 Hz), 3.09 (2H, t, CH2Ph,
Jϭ7.3 Hz), 3.54 (2H, dt, CH2CH2NH, Jϭ6.2, 6.8 Hz), 3.89 (3H, s, OCH3),
4.30 (2H, t, NCH2, Jϭ7.3 Hz), 5.42 (1H, br s, NH), 6.73 (1H, s, H2), 6.88
(1H, dd, H6, Jϭ2.3, 8.9 Hz), 7.00—7.12 (3H, m, Harom), 7.19—7.32 (4H, m,
Harom). 13C-NMR d: 14.5 (q), 20.5 (t), 23.2 (t), 36.5 (t), 39.5 (t), 42.3 (t),
48.2 (t), 55.7 (q), 100.6 (d), 110.2 (d), 110.7 (s), 112.4 (d), 126.5 (d), 126.7
(d), 128.6 (d), 128.8 (s), 131.6 (s), 138.5 (d), 153.6 (s), 169.9 (s). Anal.
Calcd for C23H28N2O2: C, 75.79; H, 7.74; N, 6.89. Found: C, 75.68; H, 7.80;
N, 6.81.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]ethyl}cyclopropanecar-
boxamide (9d): Off-yellow solid, 39%. mp 124—126 °C. 1H-NMR d:
0.59—0.73 (2H, m, cycloprop.), 0.90—1.00 (2H, m, cycloprop.), 1.10—
1.27 (1H, m, COCH cycloprop.), 2.86 (2H, t, CH2CH2NH, Jϭ6.9 Hz), 3.08
(2H, t, CH2Ph, Jϭ7.3 Hz), 3.51 (2H, dt, CH2CH2NH, Jϭ5.9, 7.0 Hz), 3.87
(3H, s, OCH3), 4.27 (2H, t, NCH2, Jϭ7.3 Hz), 5.55 (1H, br s, NH), 6.70
(1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.3, 8.9 Hz), 7.00—7.10 (3H, m, Harom),
7.19—7.32 (4H, m, Harom). 13C-NMR d: 6.7 (t), 16.5 (d), 23.2 (t), 36.5 (t),
39.5 (t), 48.2 (t), 55.7 (q), 100.6 (d), 110.2 (d), 110.7 (s), 112.4 (d), 126.5
(s), 126.7 (d), 128.6 (d), 128.8 (s), 131.6 (s), 138.5 (d), 153.6 (s), 169.9 (s).
Anal. Calcd for C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found: C, 76.01; H,
7.18; N, 7.78.
N-{2-[1-(2-Phenethyl)-1H-indol-3-yl]ethyl}propionamide (8b): Off-white
1
solid, 28%. mp 124—126 °C. H-NMR d: 1.10 (3H, t, CH2CH3, Jϭ7.3 Hz),
2.11 (2H, q, CH2CH3, Jϭ7.3 Hz), 2.91 (2H, t, CH2CH2NH, Jϭ6.6 Hz), 3.09
(2H, t, CH2Ph, Jϭ7.3 Hz), 3.53 (2H, dt, CH2CH2NH, Jϭ6.2, 6.8 Hz), 4.31
(2H, t, NCH2, Jϭ7.3 Hz), 5.45 (1H, br s, NH), 6.74 (1H, s, H2), 7.03—7.29
(7H, m, Harom), 7.34 (1H, d, H7, Jϭ8.0 Hz), 7.59 (1H, d, H4, Jϭ7.7 Hz). 13C-
NMR d: 9.8 (q), 25.1 (t), 29.6 (t), 36.7 (t), 39.5 (t), 48.6 (t), 106.8 (s), 111.1
(d), 119.6 (d), 120.5 (d), 121.7 (d), 124.1 (d), 126.6 (d), 127.5 (s), 127.7 (d),
128.5 (d), 135.3 (s), 137.8 (s), 170.0 (s). Anal. Calcd for C21H24N2O: C,
78.72; H, 7.55; N, 8.74. Found: C, 78.67; H, 7.53; N, 8.80.
N-{2-[1-(2-Phenethyl)-1H-indol-3-yl]ethyl}butyramide (8c): Beige solid,
1
34%. mp 127—129 °C. H-NMR d: 0.91 (3H, t, CH2CH3, Jϭ7.3 Hz), 1.61
(2H, sextet, CH2CH2CH3, Jϭ7.3 Hz), 2.06 (2H, t, COCH2, Jϭ7.3 Hz), 2.90
(2H, t, CH2CH2NH, Jϭ6.6 Hz), 3.08 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.53 (2H,
dt, CH2CH2NH, Jϭ6.2, 6.8 Hz), 4.31 (2H, t, NCH2, Jϭ7.3 Hz), 5.42 (1H, br
s, NH), 6.74 (1H, s, H2), 7.02—7.30 (7H, m, Harom), 7.34 (1H, d, H7,
Jϭ8.0 Hz), 7.60 (1H, d, H4, Jϭ8.0 Hz). 13C-NMR d: 13.6 (q), 19.0 (t), 25.3
(t), 36.7 (t), 38.6 (t), 39.7 (t), 48.5 (t), 106.8 (s), 110.9 (d), 119.6 (d), 120.4
(d), 121.5 (d), 124.1 (d), 126.6 (d), 127.5 (s), 127.8 (d), 128.5 (d), 135.4 (s),
137.9 (s), 170.2 (s). Anal. Calcd for C22H26N2O: C, 79.01; H, 7.84; N, 8.38.
Found: C, 78.85; H, 7.80; N, 8.42.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]ethyl}cyclobutanecar-
1
boxamide (9e): Yellowish solid, 32%. mp 95—97 °C. H-NMR d: 1.80—
2.30 (6H, m, cyclobut.), 2.71—2.92 (3H, m, COCH cyclobut.ϩ
CH2CH2NH), 3.02 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.51 (2H, dt, CH2CH2NH,
Jϭ5.9, 7.0 Hz), 3.87 (3H, s, OCH3), 4.26 (2H, t, NCH2, Jϭ7.3 Hz), 5.52
(1H, br s, NH), 6.70 (1H, s, H2), 6.90 (1H, dd, H6, Jϭ2.6, 8.8 Hz), 7.00—
7.10 (3H, m, Harom), 7.19—7.32 (4H, m, Harom). 13C-NMR d: 20.1 (t), 23.0
(t), 27.2 (t), 36.6 (t), 39.5 (d), 42.4 (t), 48.2 (t), 55.7 (q), 100.6 (d), 110.2 (d),
110.6 (s), 112.6 (d), 126.5 (s), 126.7 (d), 128.6 (d), 128.9 (s), 131.6 (s),
138.5 (d), 153.5 (s), 169.7 (s). Anal. Calcd for C24H28N2O2: C, 76.56; H,
7.50; N, 7.44. Found: C, 76.48; H, 7.55; N, 7.38.
N-{2-[1-(2-Phenethyl)-1H-indol-3-yl]ethyl}cyclopropanecarboxamide
(8d): Pale yellow solid, 40%. mp 149—151 °C. 1H-NMR d: 0.60—0.75 (2H,
m, cycloprop.), 0.87—1.01 (2H, m, cycloprop.), 1.10—1.30 (1H, m, COCH
cycloprop.), 2.89 (2H, t, CH2CH2NH, Jϭ6.6 Hz), 3.07 (2H, t, CH2Ph,
Jϭ7.3 Hz), 3.52 (2H, dt, CH2CH2NH, Jϭ5.9, 7.0 Hz), 4.29 (2H, t, NCH2,
Jϭ7.3 Hz), 5.77 (1H, br s, NH), 6.73 (1H, s, H2), 7.00—7.28 (7H, m, Harom),
7.33 (1H, d, H7, Jϭ8.4 Hz), 7.60 (1H, d, H4, Jϭ7.7 Hz). 13C-NMR d: 6.7 (t),
14.5 (d), 25.2 (t), 29.6 (t), 36.6 (t), 39.7 (t), 48.5 (t), 106.7 (s), 110.9 (d),
119.7 (d), 120.5 (d), 121.4 (d), 124.2 (d), 126.5 (d), 127.5 (s), 127.9 (d),
128.4 (d), 135.4 (s), 137.8 (s), 170.1 (s). Anal. Calcd for C22H24N2O: C,
79.48; H, 7.28; N, 8.43. Found: C, 79.35; H, 7.25; N, 8.50.
N-{2-[1-(2-Phenethyl)-1H-indol-3-yl]ethyl}cyclobutanecarboxamide (8e):
Beige solid, 23%. mp 112—114 °C. 1H-NMR d: 1.58—2.38 (6H, m, cy-
clobut.), 2.75—2.98 (3H, m, COCH cyclobut.ϩCH2CH2NH), 3.08 (2H, t,
CH2Ph, Jϭ7.3 Hz), 3.52 (2H, dt, CH2CH2NH, Jϭ5.9, 7.0 Hz), 4.31 (2H, t,
NCH2, Jϭ7.3 Hz), 5.36 (1H, br s, NH), 6.74 (1H, s, H2), 7.02—7.30 (7H, m,
Harom), 7.34 (1H, d, H7, Jϭ7.7 Hz), 7.59 (1H, d, H4, Jϭ8.0 Hz). 13C-NMR d:
17.9 (t), 25.0 (t), 25.3 (t), 36.7 (t), 39.6 (t), 39.8 (d), 48.7 (t), 106.6 (s), 110.8
(d), 119.6 (d), 120.4 (d), 121.4 (d), 124.1 (d), 126.6 (d), 127.5 (s), 127.8 (d),
128.3 (d), 135.5 (s), 137.7 (s), 170.0 (s). Anal. Calcd for C23H26N2O: C,
79.73; H, 7.56; N, 8.09. Found: C, 79.68; H, 7.59; N, 8.12.
5-Methoxy-1-(2-phenethyl)-1H-indole-3-carboxaldehyde (11) A solu-
tion of the tosylate 5 (4.04 g, 14.64 mmol) in acetonitrile (5 ml) was added
dropwise to a refluxing, stirred suspension of 5-methoxyidole-3-carboxalde-
hyde (10) (1.31 g, 7.49 mmol) and potassium carbonate (6.20 g, 44.93 mmol)
in acetonitrile (30 ml). The mixture was refluxed for 5 h, cooled to room
temperature and then poured into ice-water. The solution was stirred for
30 min, AcOEt was added and the mixture separated. The organic layer was
washed with water and brine and dried over Na2SO4. The solvent was re-
moved under vacuum and the residue was purified by flash chromatography
using cyclohexane/AcOEtϭ70 : 30 to give aldehyde 11 as an off-white solid.
mp 96—97 °C (hexane/ethyl acetate). 1H-NMR d: 3.14 (2H, t, CH2Ph,
Jϭ6.9 Hz), 3.91 (3H, s, OCH3), 4.37 (2H, t, NCH2, Jϭ6.9 Hz), 6.93—7.06
(3H, m, Harom), 7.20—7.31 (4H, m, Harom), 7.35 (1H, s, H2), 7.80 (1H, d,
Harom, Jϭ2.4 Hz), 9.85 (1H, s, CHO). 13C-NMR d: 36.1 (t), 49.0 (t), 55.7 (q),
103.4 (d), 110.7 (d), 114.4 (d), 117.6 (s), 126.1 (s), 127.0 (d), 128.6 (d),
128.7 (d), 131.7 (s), 137.4 (s), 138.7 (d), 156.6 (s), 184.4 (d). Anal. Calcd
for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.80; H, 6.21; N,
4.96.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]ethyl}acetamide (9a):
White solid, 50%. mp 135—137 °C. 1H-NMR d: 1.91 (3H, s, COCH3), 2.86
(2H, t, CH2CH2NH, Jϭ6.9 Hz), 3.08 (2H, t, CH2Ph, Jϭ6.6 Hz), 3.51 (2H,
dt, CH2CH2NH, Jϭ6.2, 6.8 Hz), 3.87 (3H, s, OCH3), 4.28 (2H, t, NCH2,
Jϭ7.3 Hz), 5.40 (1H, br s, NH), 6.70 (1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.2,
8.8 Hz), 7.00—7.10 (3H, m, Harom), 7.19—7.32 (4H, m, Harom). 13C-NMR d:
23.5 (q), 25.1 (t), 36.7 (t), 39.8 (t), 48.2 (t), 55.9 (q), 100.6 (d), 110.3 (d),
110.9 (s), 112.5 (d), 126.5 (d), 126.7 (d), 128.6 (d), 128.8 (s), 131.4 (s),
138.6 (d), 153.9 (s), 169.9 (s). Anal. Calcd for C21H24N2O2: C, 74.97; H,
7.19; N, 8.33. Found: C, 74.67; H, 7.23; N, 8.24.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]ethyl}propionamide
(9b): White solid, 23%. mp 102—104 °C. 1H-NMR d: 1.11 (3H, t, CH2CH3,
Jϭ7.7 Hz), 2.12 (2H, q, CH2CH3, Jϭ7.7 Hz), 2.87 (2H, t, CH2CH2NH,
Jϭ6.9 Hz), 3.07 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.52 (2H, dt, CH2CH2NH,
Jϭ6.2, 6.8 Hz), 3.87 (3H, s, OCH3), 4.28 (2H, t, NCH2, Jϭ7.3 Hz), 5.42
5-Methoxy-3-(2-nitropropen-1-yl)-1-(2-phenethyl)-1H-indole (12)
A
solution of the aldehyde 11 (2.62 g, 9.39 mmol) and ammonium acetate
(0.92 g, 11.95 mmol) in nitroethane (33 ml) was refluxed for 4 h. After evap-
oration of the solvent under reduced pressure, the residue was dissolved in
dichloromethane and water was added. The aqueous layer was washed with
dichloromethane and the combined organic layers were washed with water
and brine and dried over Na2SO4. Removal of the solvent in vacuo gave a
dark orange residue which was triturated with AcOEt. The title compound
1
12 was obtained as an orange powder. mp 126—127 °C. H-NMR d: 2.30
(3H, s, CH3), 3.12 (2H, t, CH2Ph, Jϭ6.9 Hz), 3.91 (3H, s, OCH3), 4.40 (2H,
t, NCH2, Jϭ6.9 Hz), 6.94—7.02 (4H, m, Harom), 7.20—7.31 (5H, m, Harom),
8.45 (1H, s, CHϭC-NO2). 13C-NMR d: 14.7 (q), 36.4 (t), 49.1 (t), 55.9 (q),
100.4 (d), 108.2 (s), 110.9 (d), 114.0 (d), 126.4 (d), 127.0 (d), 128.8 (d),
129.4 (s), 130.8 (s), 131.0 (d), 137.7 (d), 141.1 (s), 155.7 (s). Anal. Calcd for
C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.30; H, 5.92; N, 8.14.

January 2002
37
1-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-propionamine (13)
A
for 4 h, the reaction mixture was treated with saturated NH4Cl (5 ml) and ex-
solution of 12 (0.29 g, 0.86 mmol) in THF (4 ml) was added dropwise at 0 °C tracted with AcOEt. The extract was washed with water and brine, dried
to a stirred suspension of lithium aluminum hydride (0.17 g, 4.40 mmol) in over Na2SO4 and the solvent removed in vacuo. The crude product formed
THF (5 ml). The mixture was refluxed for 4 h and then allowed to reach am-
was flash chromatographed eluting with cyclohexane/AcOEtϭ97 : 3 to give
1
bient temperature. After cooling to 0 °C, water (4 ml) was cautiously added. 0.40 g (71%) of 15 as an off white solid. mp 67—68 °C. H-NMR d: 1.61
The resultant mixture was filtered through Celite and the filtrate was taken (3H, d, CHCH3, Jϭ6.9 Hz), 2.97 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.82 (3H, s,
up in AcOEt. The organic layer was sequentially washed with water and OCH3), 3.99 (1H, q, CHCH3, Jϭ6.9 Hz), 4.17 (2H, t, NCH2, Jϭ7.3 Hz),
brine and dried over Na2SO4. The solvent was removed under vacuum to 6.78 (1H, s, H2), 6.88 (1H, dd, H6, Jϭ2.2, 8.8 Hz), 6.93—7.07 (3H, m,
give 0.25 g (96%) of the amine 13 as a pale yellow oil, which was used in
the next step without further purification.
Harom), 7.10—7.28 (4H, m, Harom). 13C-NMR d: 19.7 (q), 22.7 (d), 36.7 (t),
48.4 (t), 55.9 (q), 101.8 (d), 110.6 (d), 112.3 (d), 114.6 (s), 124.5 (s), 124.8
Preparation of the amides 14a—e These were prepared by the same (s), 125.5 (s), 126.7 (d), 128.6 (d), 128.7 (s), 131.9 (s), 138.2 (d), 153.9 (s).
method used for the synthesis of amides 8a—e and 9a—e.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-1-methylethyl}ac-
etamide (14a): Beige amorphous solid, 44%. mp 127—128 °C. H-NMR d:
1.07 (3H, d, CHCH3, Jϭ6.9 Hz), 1.89 (3H, s, CH3CO), 2.83 (2H, d, CH2CH, amine was prepared by the method described for 7a. Yellow oil, 98%.
Anal. Calcd for C20H20N2O: C, 78.92; H, 6.62; N, 9.20. Found: C, 78.75; H,
6.49; N, 8.81.
2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propionamine (16) This
1
Jϭ5.1 Hz), 3.08 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.88 (3H, s, OCH3), 4.22—4.40
Preparation of the amides 17a—e These were prepared by the same
(3H, m, NCH2ϩCHCH3), 5.24 (1H, br s, NH), 6.65 (1H, s, H2), 6.88 (1H, method used for the synthesis of amides 8a—e and 9a—e.
dd, H6, Jϭ2.2, 8.8 Hz), 6.99—7.12 (3H, m, Harom), 7.17—7.32 (4H, m,
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propyl}acetamide (17a):
Harom). 13C-NMR d: 20.0 (q), 23.7 (q), 31.4 (d), 36.6 (t), 45.3 (t), 48.2 (t), Beige amorphous solid, 42%. mp 101—103 °C. 1H-NMR d: 1.26 (3H, d,
55.9 (q), 100.8 (d), 109.5 (d), 110.1 (d), 111.9 (d), 126.6 (s), 127.2 (d), CHCH3, Jϭ6.6 Hz), 1.86 (3H, s, COCH3), 3.06 (2H, t, CH2Ph, Jϭ7.3 Hz),
128.5 (d), 128.8 (s), 129.1 (s), 138.6 (d), 153.9 (s), 169.2 (s). Anal. Calcd for 3.12—3.38 (1H, m, CHCH3), 3.48—3.67 (2H, m, CH2NH), 3.86 (3H, s,
C22H26N2O2: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.10; H, 7.45; N, 7.68.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-1-methylethyl}propi-
OCH3), 4.27 (2H, t, NCH2, Jϭ7.3 Hz), 5.30 (1H, br s, NH), 6.63 (1H, s, H2),
6.88 (1H, dd, H6, Jϭ2.2, 8.4 Hz), 6.97—7.08 (3H, m, Harom), 7.14—7.28
onamide (14b): Beige amorphous solid, 25%. mp 112—113 °C. 1H-NMR d: (4H, m, Harom). 13C-NMR d: 18.4 (q), 22.6 (q), 30.5 (d), 36.8 (t), 45.5 (t),
1.08 (3H, d, CHCH3, Jϭ7.7 Hz), 1.10 (3H, t, CH2CH3, Jϭ7.7 Hz), 2.10 (2H, 48.4 (t), 55.4 (q), 101.0 (d), 110.2 (d), 111.9 (d), 116.6 (s), 125.1 (d), 126.6
q, CH2CH3, Jϭ7.7 Hz), 2.83 (2H, d, CH2CH, Jϭ4.8 Hz), 3.08 (2H, t, (s), 127.6 (d), 128.5 (d), 128.7 (s), 131.4 (s), 138.5 (d), 153.7 (s), 172.8 (s).
CH2Ph, Jϭ7.3 Hz), 3.85 (3H, s, OCH3), 4.21—4.37 (3H, m, NCH2ϩ Anal. Calcd for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.25; H,
CHCH3), 5.23 (1H, br s, NH), 6.67 (1H, s, H2), 6.87 (1H, dd, H6, Jϭ2.6,
9.1 Hz), 7.01—7.09 (3H, m, Harom), 7.18—7.30 (4H, m, Harom). 13C-NMR d:
9.7 (q), 20.0 (q), 29.6 (t), 31.4 (d), 36.5 (t), 45.0 (t), 48.0 (t), 55.8 (q), 101.0
(d), 109.4 (d), 110.1 (d), 112.0 (d), 126.5 (s), 127.5 (d), 128.5 (d), 128.8 (s),
129.0 (s), 138.6 (d), 154.0 (s), 169.0 (s). Anal. Calcd for C23H28N2O2: C,
75.79; H, 7.74; N, 7.69. Found: C, 75.59; H, 7.68; N, 7.31.
7.48; N, 7.62.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propyl}propionamide
(17b): Beige amorphous solid, 39%. mp 103—104 °C. 1H-NMR d: 1.07
(3H, t, CH2CH3, Jϭ7.7 Hz), 1.28 (3H, d, CHCH3, Jϭ6.6 Hz), 2.09 (2H, q,
CH2CH3, Jϭ7.7 Hz), 3.07 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.14—3.40 (1H, m,
CHCH3), 3.54—3.69 (2H, m, CH2NH), 3.87 (3H, s, OCH3), 4.28 (2H, t,
NCH2, Jϭ7.3 Hz), 5.33 (1H, br s, NH), 6.65 (1H, s, H2), 6.89 (1H, dd, H6,
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-1-methylethyl}butyr-
1
amide (14c): Beige amorphous solid, 29%. mp 116—117 °C. H-NMR d: Jϭ2.2, 8.8 Hz), 7.00—7.09 (3H, m, Harom), 7.20—7.32 (4H, m, Harom). 13C-
0.91 (3H, t, CH2CH3, Jϭ7.3 Hz), 1.09 (3H, d, CHCH3, Jϭ6.6 Hz), 1.62 (2H, NMR d: 9.7 (q), 18.7 (q), 29.5 (t), 30.8 (d), 36.5 (t), 45.7 (t), 48.5 (t), 55.3
sextet, CH2CH2CH3, Jϭ7.3 Hz), 2.05 (2H, t, COCH2, Jϭ7.3 Hz), 2.80— (q), 101.2 (d), 110.0 (d), 112.0 (d), 116.5 (s), 125.1 (d), 126.5 (s), 127.6 (d),
2.87 (2H, m, CH2CH), 3.08 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.88 (3H, s, OCH3), 128.5 (d), 128.7 (s), 131.3 (s), 138.5 (d), 153.5 (s), 173.0 (s). Anal. Calcd for
4.22—4.37 (3H, m, NCH2ϩCHCH3), 5.27 (1H, br s, NH), 6.68 (1H, s, H2), C23H28N2O2: C, 75.79; H, 7.74; N, 7.69. Found: C, 75.65; H, 7.84; N, 7.47.
6.89 (1H, dd, H6, Jϭ2.2, 8.8 Hz), 7.03—7.09 (3H, m, Harom), 7.20—7.29
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propyl}butyramide
(4H, m, Harom). 13C-NMR d: 13.6 (q), 19.0 (q), 20.0 (t), 31.4 (d), 36.8 (t), (17c): Beige amorphous solid, 77%. mp 116—118 °C. 1H-NMR d: 0.89
45.4 (t), 48.4 (t), 56.0 (q), 100.8 (d), 109.7 (d), 110.2 (d), 112.0 (d), 126.6 (3H, t, CH2CH3, Jϭ7.3 Hz), 1.29 (3H, d, CHCH3, Jϭ6.6 Hz), 1.50—1.70
(s), 127.0 (d), 128.7 (d), 128.9 (s), 130.0 (s), 138.4 (d), 153.7 (s), 169.4 (s). (2H, m, CH2CH3), 2.03 (2H, t, COCH2, Jϭ6.9 Hz), 3.07 (2H, t, CH2Ph,
Anal. Calcd for C24H30N2O2: C, 76.16; H, 8.00; N, 7.40. Found: C, 75.77; H,
8.02; N, 7.14.
Jϭ7.3 Hz), 3.15—3.44 (1H, m, CHCH3), 3.51—3.68 (2H, m, CH2NH), 3.87
(3H, s, OCH3), 4.28 (2H, t, NCH2, Jϭ7.3 Hz), 5.36 (1H, br s, NH), 6.65
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-1-methylethyl}cyclo- (1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.6, 8.8 Hz), 7.00—7.13 (3H, m, Harom),
propanecarboxamide (14d): Beige amorphous solid, 33%. mp 119—120 °C.
7.19—7.34 (4H, m, Harom). 13C-NMR d: 13.6 (q), 18.4 (q), 20.6 (t), 29.5 (t),
1H-NMR d: 0.66—0.72 (2H, m, cycloprop.), 0.91—1.02 (2H, m, cyclo- 30.5 (d), 36.7 (t), 45.3 (t), 48.2 (t), 55.5 (q), 100.9 (d), 110.2 (d), 112.2 (d),
prop.), 1.08 (3H, d, CHCH3, Jϭ7.0 Hz), 1.13—1.20 (1H, m, COCH cyclo- 116.8 (s), 125.1 (d), 126.6 (s), 127.8 (d), 128.5 (d), 128.7 (s), 131.0 (s),
prop.), 2.85 (2H, d, CH2CH, Jϭ5.5 Hz), 3.08 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.88 138.7 (d), 153.6 (s), 172.8 (s). Anal. Calcd for C24H30N2O2: C, 76.16; H,
(3H, s, OCH3), 4.23—4.38 (3H, m, NCH2ϩCHCH3), 5.43 (1H, br s, NH), 8.00; N, 7.40. Found: C, 76.06; H, 8.03; N, 7.07.
6.69 (1H, s, H2), 6.88 (1H, dd, H6, Jϭ2.6, 9.2 Hz), 7.02—7.09 (3H, m,
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propyl}cyclopropane-
Harom), 7.19—7.30 (4H, m, Harom). 13C-NMR d: 6.7 (t), 14.5 (d), 20.0 (q),
carboxamide (17d): Beige amorphous solid, 80%. mp 186—188 °C. 1H-
31.4 (d), 36.7 (t), 45.3 (t), 48.2 (t), 55.8 (q), 100.7 (d), 109.5 (d), 110.1 (d), NMR d: 0.61—0.72 (2H, m, cycloprop.), 0.87—1.00 (2H, m, cycloprop.),
111.8 (d), 126.6 (s), 127.2 (d), 128.5 (d), 128.8 (s), 129.1 (s), 138.6 (d),
153.9 (s), 169.2 (s). Anal. Calcd for C24H28N2O2: C, 76.56; H, 7.50; N, 7.44.
Found: C, 76.46; H, 7.55; N, 7.24.
1.09—1.21 (1H, m, COCH cycloprop.), 1.29 (3H, d, CHCH3, Jϭ6.6 Hz),
3.08 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.14—3.38 (1H, m, CHCH3), 3.58—3.74
(2H, m, CH2NH), 3.87 (3H, s, OCH3), 4.29 (2H, t, NCH2, Jϭ7.3 Hz), 5.53
(1H, br s, NH), 6.68 (1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.6, 9.1 Hz), 7.00—
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-1-methylethyl}cyclobu-
tanecarboxamide (14e): Beige amorphous solid, 22%. mp 116—117 °C. 1H- 7.11 (3H, m, Harom), 7.19—7.29 (4H, m, Harom). 13C-NMR d: 6.7 (t), 14.5
NMR d: 1.07 (3H, d, CHCH3, Jϭ6.9 Hz), 1.74—2.37 (6H, m, cyclobut.),
2.71—2.92 (3H, m, CH2CHϩCOCH cyclobut.), 3.06 (2H, t, CH2Ph,
(d), 18.4 (q), 30.5 (d), 36.8 (t), 45.5 (t), 48.4 (t), 55.4 (q), 101.3 (d), 110.4
(d), 111.9 (d), 116.4 (s), 125.1 (d), 126.6 (s), 127.3 (d), 128.5 (d), 128.7 (s),
Jϭ7.3 Hz), 3.87 (3H, s, OCH3), 4.14—4.37 (3H, m, NCH2ϩCHCH3), 5.20 131.3 (s), 138.6 (d), 153.4 (s), 172.8 (s). Anal. Calcd for C24H28N2O2: C,
(1H, br s, NH), 6.67 (1H, s, H2), 6.87 (1H, dd, H6, Jϭ2.6, 8.8 Hz), 6.99—
76.56; H, 7.50; N, 7.44. Found: C, 76.50; H, 7.83; N, 7.04.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propyl}cyclobutanecar-
7.09 (3H, m, Harom), 7.16—7.31 (4H, m, Harom). 13C-NMR d: 18.1 (t), 20.0
1
(q), 25.3 (t), 31.4 (d), 36.7 (t), 39.8 (d), 45.2 (t), 48.1 (t), 56.0 (q), 101.0 (d), boxamide (17e): Beige amorphous solid, 30%. mp 123—125 °C. H-NMR
109.4 (d), 110.1 (d), 112.2 (d), 126.5 (s), 127.2 (d), 128.5 (d), 128.8 (d), d: 1.28 (3H, d, CHCH3, Jϭ7.0 Hz), 1.74—2.29 (6H, m, cyclobut.), 2.76—
129.1 (d), 138.9 (d), 153.9 (s), 169.0 (s). Anal. Calcd for C25H30N2O2: C,
2.91 (1H, m, COCH cyclobut.), 3.01 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.15—3.39
76.89; H, 7.74; N, 7.17. Found: C, 76.69; H, 7.76; N, 6.82.
(1H, m, CHCH3), 3.50—3.71 (2H, m, CH2NH), 3.87 (3H, s, OCH3), 4.28
2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]propionitrile (15) A so- (2H, t, NCH2, Jϭ7.3 Hz), 5.24 (1H, br s, NH), 6.67 (1H, s, H2), 6.89 (1H,
lution of the acetonitrile 6b (0.54 g, 1.86 mmol) in DMF (6 ml) was added dd, H6, Jϭ2.6, 9.1 Hz), 7.01—7.14 (3H, m, Harom), 7.20—7.37 (4H, m,
dropwise at 0 °C to a stirred suspension of sodium hydride (60% dispersion Harom). 13C-NMR d: 18.1 (t), 18.4 (q), 25.3 (t), 30.5 (d), 36.7 (t), 39.8 (d),
in mineral oil, 0.05 g, 1.88 mmol) in DMF (7 ml). The reaction mixture was 45.5 (t), 48.2 (t), 55.2 (q), 101.0 (d), 110.2 (d), 111.8 (d), 116.6 (s), 125.1
then treated with methyl iodide (0.15 ml, 2.10 mmol) and left stirring at 0 °C (d), 126.6 (s), 127.5 (d), 128.5 (d), 128.6 (d), 131.6 (s), 138.4 (d), 153.7 (s),
for 30 min before it was allowed to warm to room temperature. After stirring 173.0 (s). Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C,

38
Vol. 50, No. 1
76.70; H, 7.72; N, 7.27.
1.76—2.23 (6H, m, cyclobut.), 2.71—2.86 (1H, m, COCH cyclobut.), 3.05
2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropionitrile
(2H, t, CH2Ph, Jϭ7.3 Hz), 3.56 (2H, d, CH2NH, Jϭ5.8 Hz), 3.85 (3H, s,
(18) A solution of the acetonitrile 6b (0.21 g, 0.73 mmol) and methyl io- OCH3), 4.26 (2H, t, NCH2CH2, Jϭ7.3 Hz), 5.00 (1H, br s, NH), 6.61 (1H, s,
dide (0.10 ml, 1.82 mmol) in DMF (1.5 ml) was added dropwise at 0 °C to a H2), 6.89 (1H, dd, H6, Jϭ2.5, 9.1 Hz), 7.00—7.10 (3H, m, Harom), 7.16—
stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.04 g, 7.31 (4H, m, Harom). 13C-NMR d: 18.1 (t), 25.3 (t), 26.5 (q), 35.8 (s), 36.6
1.82 mmol) in DMF (1.5 ml). The reaction mixture was then allowed to (t), 39.8 (d), 45.7 (t), 48.5 (t), 56.2 (q), 101.0 (d), 110.2 (d), 111.8 (d), 116.6
warm to room temperature. After stirring for 4 h, the reaction mixture was (s), 125.1 (s), 126.6 (d), 127.5 (d), 128.5 (d), 128.6 (s), 131.6 (s), 138.4 (d),
treated with saturated NH4Cl (5 ml) and extracted with AcOEt. The extract 153.7 (s), 173.0 (s). Anal. Calcd for C26H32N2O2: C, 77.19; H, 7.97; N, 6.52.
was washed with water and brine, dried over Na2SO4 and the solvent re- Found: C, 76.98; H, 7.92; N, 6.48.
moved in vacuo. The crude product formed was flash chromatographed elut-
Xenopus Melanophore Model for the Evaluation of Agonist and An-
ing with cyclohexane/AcOEtϭ90 : 10 to give 0.20 g (85%) of 18 as a beige tagonist Activity Melanophore cells were grown in 96-well tissue culture
solid. mp 72—73 °C (hexane/ethyl acetate). 1H-NMR d: 1.77 (6H, s, plates, and growth medium29,30) was replaced with 0.7ϫL-15 culture
C(CH3)2), 3.03 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.90 (3H, s, OCH3), 4.23 (2H, t, medium 18 h before analogs were tested. Initial absorbance of cells (Ai,
NCH2, Jϭ7.3 Hz), 6.72 (1H, s, H2), 6.92–7.05 (4H, m, Harom), 7.23—7.35 630 nm) was measured in each well using a Bio-Tek microtiter plate reader
(4H, m, Harom). 13C-NMR d: 27.8 (q), 29.7 (s), 36.6 (t), 48.4 (t), 56.0 (q), (model EL3115, Anachem, U.K.), then cells were treated with the concentra-
101.8 (d), 110.6 (d), 112.3 (d), 114.6 (s), 124.5 (s), 124.9 (s), 125.5 (s), tions of the analogs indicated. All experiments used triplicate wells at six
126.7, (d) 128.6 (d), 128.7 (s), 131.9 (s), 138.2 (d), 153.9 (s). Anal. Calcd concentrations of analog. The final absorbance (Af ) was measured after
for C21H22N2O: C, 79.21; H, 6.96; N, 8.80. Found: C, 78.95; H, 6.59; N,
8.61.
60 min, and the fractional change in absorbance (1ϪAf /Ai) was calculated.
Vehicle did not alter pigment granule distribution itself or inhibit responses
2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropionamine to melatonin. The concentration of analog producing 50% of the maximum
(19) This amine was prepared by the method described for 7a. Yellow oil, agonist response (EC50) was determined from concentration–response
95%.
curves. For evaluation of antagonist potency, cells were treated with vehicle
Preparation of the amides 20a—e These were prepared by the same (1% dimethyl sulfoxide or methanol) or varying concentrations (10Ϫ4
—
method used for the synthesis of amides 8a—e and 9a—e.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropyl}ac-
10Ϫ9 M) of the analogs for 60 min before melatonin (10Ϫ9 M) was added. The
concentration of analog reducing melatonin-induced pigment aggregation by
etamide (20a): Viscous yellow oil (flash chromatography using cyclo- 50% (IC50) was determined.
hexane/AcOEtϭ70 : 30), 45%. 1H-NMR d: 1.32 (6H, s, C(CH3)2), 1.83 (3H,
s, COCH3), 3.06 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.56 (2H, d, CH2NH, Jϭ5.9 Hz),
Acknowledgements The authors are grateful to the Ministry of Educa-
3.85 (3H, s, OCH3), 4.26 (2H, t, NCH2CH2, Jϭ7.3 Hz), 5.07 (1H, br s, NH), tion of Greece for its support to this project through the EPEAEK Program
6.58 (1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.6, 8.8 Hz), 6.99—7.08 (3H, m, (KA: 70/3/3759).
Harom), 7.14—7.31 (4H, m, Harom). 13C-NMR d: 23.4 (q), 26.5 (q), 35.7 (s),
36.8 (t), 45.3 (t), 48.9 (t), 56.0 (q), 101.0 (d), 110.2 (d), 111.9 (d), 116.6 (s), References and Notes
125.1 (s), 126.6 (d), 127.6 (d), 128.5 (d), 128.7 (s), 131.4 (s), 138.5 (d),
153.7 (s), 172.8 (s). Anal. Calcd for C23H28N2O2: C, 75.79; H, 7.74; N, 7.69.
Found: C, 75.55; H, 7.48; N, 7.52.
1) Reiter R. J., Endocr. Rev., 12, 151—180 (1991).
2) Bartness T. J., Powers J. B., Hastings M. H., Bittman E. L., Goldman
B. D., J. Pineal Res., 15, 161—190 (1993).
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropyl}propi-
onamide (20b): Viscous yellow oil (flash chromatography using cyclo-
hexane/AcOEtϭ70 : 30), 40%. 1H-NMR d: 1.04 (3H, t, CH2CH3, Jϭ7.7 Hz),
1.32 (6H, s, C(CH3)2), 2.03 (2H, q, CH2CH3, Jϭ7.7 Hz), 3.06 (2H, t, CH2Ph,
Jϭ7.3 Hz), 3.57 (2H, d, CH2NH, Jϭ5.8 Hz), 3.85 (3H, s, OCH3), 4.26 (2H,
t, NCH2CH2, Jϭ7.3 Hz), 5.05 (1H, br s, NH), 6.60 (1H, s, H2), 6.89 (1H, dd,
H6, Jϭ2.2, 8.4 Hz), 7.00—7.07 (3H, m, Harom), 7.15—7.28 (4H, m, Harom).
13C-NMR d: 10.0 (q), 26.6 (q), 29.9 (t), 35.9 (s), 36.7 (t), 45.4 (t), 48.7 (t),
56.1 (q), 101.2 (d), 110.0 (d), 112.0 (d), 116.5 (s), 125.1 (s), 126.5 (d), 127.6
(d), 128.5 (d), 128.7 (s), 131.3 (s), 138.5 (d), 153.5 (s), 173.0 (s). Anal.
Calcd for C24H30N2O2: C, 76.16; H, 7.99; N, 7.40. Found: C, 75.95; H, 7.90;
N, 7.28.
3) Reiter R. J., Experientia, 49, 654—664 (1993).
4) Krause D. N., Barrios V. E., Duckles S. P., Eur. J. Pharmacol., 276,
207—213 (1995).
5) Capsoni S., Stankov B. M., Fraschini F., Neuroreport, 6, 1346—1348
(1995).
6) Dubocovich M. L., Nature (London), 306, 782—784 (1983).
7) Dollins A. B., Zhadanova I. V., Wurtman R. J., Lynch H. J., Deng M.
H., Proc. Natl. Acad. Sci. U.S.A., 91, 1824—1828 (1994).
8) Garfinkel D., Laudon M., Nof D., Zisapel N., Lancet, 346, 541—544
(1995).
9) Reppert S. M., Godson C., Mahle C. D., Weaver D. R., Slaugenhaupt
S. A., Gusella J. F., Proc. Natl. Acad. Sci. U.S.A., 92, 8734—8738
(1995).
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropyl}butyr-
amide (20c): Viscous yellow oil (flash chromatography using cyclo- 10) Kloubert S., Mathé-Alainmat M., Andrieux J., Sicsic S., Langlois M.,
hexane/AcOEtϭ75 : 25), 43%. 1H-NMR d: 0.85 (3H, t, CH2CH3, Jϭ7.3 Hz),
Bioorg. Med. Chem. Lett., 8, 3325—3330 (1998).
1.32 (6H, s, C(CH3)2), 1.47—1.57 (2H, m, CH2CH3), 1.98 (2H, t, COCH2, 11) Heward C. B., Hadley M. E., Life Sci., 17, 1167—1177 (1975).
Jϭ7.3 Hz), 3.06 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.57 (2H, d, CH2NH, Jϭ5.8 Hz), 12) Sugden D., Chong N. W. S., Brain Res., 539, 151—154 (1991).
3.85 (3H, s, OCH3), 4.26 (2H, t, NCH2CH2, Jϭ7.3 Hz), 5.05 (1H, br s, NH), 13) Depreux P., Lesieur D., Mansour H. A., Morgan P., Howell H. E., Re-
6.60 (1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.2, 8.8 Hz), 6.99—7.08 (3H, m,
Harom), 7.14—7.28 (4H, m, Harom). 13C-NMR d: 13.7 (q), 19.2 (t), 26.5 (q),
35.7 (t), 36.9 (t), 38.8 (s), 45.8 (t), 48.6 (t), 56.1 (q), 100.9 (d), 110.2 (d),
nard P., Caignard D. H., Pfeiffer B., Delagrange P., Guardiola B., Yous
S., Demarque A., Adam G., Andrieux J., J. Med. Chem., 37, 3231—
3239 (1994).
112.2 (d), 116.8 (s), 125.1 (s), 126.6 (d), 127.8 (d), 128.5 (d), 128.7 (s), 14) Garratt P. J., Travard S., Vonhoff S., Tsotinis A., Sugden D., J. Med.
131.0 (s), 138.7 (d), 153.6 (s), 172.8 (s). Anal. Calcd for C25H32N2O2: C,
76.50; H, 8.22; N, 7.14. Found: C, 76.35; H, 8.18; N, 7.07.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropyl}cyclo-
Chem., 39, 1797—1805 (1996).
15) Navajas C., Kokkola T., Poso A., Honka N., Gynther J., Laitinen J. T.,
Eur. J. Pharmacol., 304, 173—183 (1996).
propanecarboxamide (20d): Viscous yellow oil (flash chromatography using 16) Garratt P. J., Jones R., Rowe S. J., Sugden D., Bioorg. Med. Chem.
1
cyclohexane/AcOEtϭ75 : 25), 38%. H-NMR d: 0.60—0.65 (2H, m, cyclo-
Lett., 4, 1555—1558 (1994).
prop.), 0.87—0.92 (2H, m, cycloprop.), 1.06—1.12 (1H, m, COCH cyclo- 17) Mor M., Rivara S., Silva C., Bordi F., Plazzi P. V., Spadoni G., Dia-
prop.), 1.33 (6H, s, C(CH3)2), 3.06 (2H, t, CH2Ph, Jϭ7.3 Hz), 3.58 (2H, d,
CH2NH, Jϭ5.8 Hz), 3.85 (3H, s, OCH3), 4.26 (2H, t, NCH2CH2, Jϭ7.3 Hz),
mantini G., Balsamini C., Tarzia G., Fraschini F., Lucini V., Nonno R.,
Stankov B. M., J. Med. Chem., 41, 3831—3844 (1998).
5.25 (1H, br s, NH), 6.61 (1H, s, H2), 6.89 (1H, dd, H6, Jϭ2.5, 8.7 Hz), 18) Garratt P. J., Jones R., Tocher D. A., Sugden D., J. Med. Chem., 38,
7.02—7.06 (3H, m, Harom), 7.18—7.27 (4H, m, Harom). 13C-NMR d: 6.7 (t),
1132—1139 (1995).
14.5 (d), 26.5 (q), 35.8 (s), 36.7 (t), 45.6 (t), 48.5 (t), 56.2 (q), 101.3 (d), 19) Tarzia G., Diamantini G., Mor M., Spadoni G., Farmaco, 55, 184—
110.4 (d), 111.9 (d), 116.4 (s), 125.1 (s), 126.6 (d), 127.3 (d), 128.5 (d), 187 (2000).
128.7 (s), 131.3 (s), 138.6 (d), 153.4 (s), 172.8 (s). Anal. Calcd for 20) Langlois M., Brémont B., Shen S., Poncet A., Andrieux J., Sicsic S.,
C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C, 76.70; H, 7.69; N, 7.09.
N-{2-[5-Methoxy-1-(2-phenethyl)-1H-indol-3-yl]-2-methylpropyl}cyclo-
Serraz I., Mathé-Allainmat M., Renard P., Delagrange P., J. Med.
Chem., 38, 2050—2060 (1995).
butanecarboxamide (20e): Viscous yellow oil (flash chromatography using 21) Frohn M. A., Seaborn C. J., Johnson D. W., Life Sci., 27, 2043—2046
cyclohexane/AcOEtϭ80 : 20), 35%. 1H-NMR d: 1.32 (6H, s, C(CH3)2),
(1980).

January 2002
39
22) Mathé-Allainmat M., Le Gall M., Jellimann C., Andrieux J., Langlois
M., Bioorg. Med. Chem., 7, 2945—2952 (1999).
522—528 (1998).
27) Conway S., Mowat E. S., Drew J. E., Barrett P., Delagrange P., Morgan
23) Faust R., Garratt P. J., Jones R., Yeh L.-K., Tsotinis A., Panous-
P. J., Biochem. Biophys. Res. Commun., 282, 1229—1236 (2001).
sopoulou M., Calogeropoulou T., Teh M.-T., Sugden D., J. Med. 28) Leclerc V., Fourmaintraux E., Depreux P., Lesieur D., Morgan P., How-
Chem., 43, 1050—1061 (2000).
24) Pérez-Alvarez V., Morales-Ríos M. S., Hong E., Joseph-Nathan P., J.
Pharm. Pharmacol., 49, 246—252 (1997).
ell H. E., Renard P., Caignard D.-H., Pfeiffer B., Delagrange P.,
Guardiola-Lemaitre B., Andrieux J., Bioorg. Med. Chem., 6, 1875—
1887 (1998).
25) Iwao M., Motoi O., Fukuda T., Ishibashi F., Tetrahedron, 54, 8999—
9010 (1998).
29) Daniolos A., Lerner A. B., Lerner M. R., Pigment Cell Res., 3, 38—43
(1990).
26) Sugden D., Teh M.-T., Naunyn Schmiedebergs Arch. Pharmacol., 358,
30) Potenza M. N., Lerner M. R., Pigment Cell Res., 5, 372—378 (1992).