Novel coumarin glycoside and phenethyl vanillate from Notopterygium forbesii and their binding affinities for opioid and dopamine receptors

Article abstract of DOI:10.1016/j.bmc.2007.12.021

Bioactivity-guided fractionation of Notopterygium forbesii has resulted in the isolation of one new coumarin glycoside and one new phenethyl vanillate, together with seventeen known compounds. The structures of these compounds were characterized by spectr

Full text of DOI:10.1016/j.bmc.2007.12.021

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 3218–3223
Novel coumarin glycoside and phenethyl vanillate from
Notopterygium forbesii and their binding affinities for opioid
and dopamine receptors
Zhongze Ma,a Wei Xu,b Lee-Yuan Liu-Chenb and David Y. W. Leea,*
aBio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School,
115 Mill Street, Belmont, MA 02478, USA
bDepartment of Pharmacology and Center for Substance Abuse Research, School of Medicine, Temple University,
3420 N. Broad Street, Philadelphia, PA 19140, USA
Received 4 October 2007; revised 6 December 2007; accepted 11 December 2007
Available online 31 December 2007
Abstract—Bioactivity-guided fractionation of Notopterygium forbesii has resulted in the isolation of one new coumarin glycoside
and one new phenethyl vanillate, together with seventeen known compounds. The structures of these compounds were characterized
by spectroscopic methods. These compounds were evaluated for their binding affinities to the opioid and dopamine receptors, and
falcarindiol showed weak binding affinities to opioid receptors and moderate affinity for D1 receptor (Ki = 192 6 nM).
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
roles in many physiological functions.4 The mu (l) opi-
oid receptor (MOR), delta (d) opioid receptor (DOR),
and kappa (j) opioid receptor (KOR) are three main
types of opioid receptors.4 These receptors are differen-
tiated by distinct genes and proteins, tissue expression
patterns, functional properties, and pharmacological
profiles of selective agonists and antagonists.5 They
are distributed throughout the central and peripheral
nervous system and are involved in a variety of physi-
ological processes, especially analgesia.6,7
Alcohol and drug abuse pose serious medical, social,
and economic problems in the United States and
around the world.1 A great deal of effort has been di-
rected toward developing effective therapies, however,
the complexity of drug dependence and the lack of
effective remediation, especially for relapse, which is of-
ten precipitated by withdrawal and/or intense craving
even after prolonged abstinence, pose a serious thera-
peutic challenge. In a consortium effort focusing on a
systematic evaluation of Traditional Chinese Medicine
for rescuing opium smoker has resulted in the isolation
and identification of certain natural products with
moderate to significant binding activities toward opioid
receptors. Notopterygium forbesii is one of the five Chi-
nese herbs in a formula (we call it as ‘NPI-025’) used
clinically to treat heroin addiction in Hong Kong.2,3
Heroin acts on opioid receptors to produce its pharma-
cological effects including mood changes, pain modula-
tion, and addiction. Opioid receptors play important
Mesolimbic dopaminergic system has been shown to
play a central role in reward system, which is usurped
by drugs of abuse in drug addiction. Dopamine (DA)
receptors belong to a family of large proteins charac-
terized by having seven relatively hydrophobic seg-
ments that are assumed to be cell-membrane
spanning.8 There are five major DA receptor subtypes
(D1–D5) with distinct differences in their gene and
peptide composition, molecular functions, and neuro-
pharmacology.8 The D1 receptor is the most abundant
DA receptor subtype in mammalian forebrain.8 Com-
pounds targeted to these DA receptor membrane pro-
teins can activate or inhibit their biological functions
as well as provide a rational treatment for drug
abuse.8
Keywords: Notopterygium forbesii; Coumarin; Falcarindiol; Opioid
receptor; Dopamine receptor.
*
Corresponding author. Tel.: +1 617 855 2038; fax: +1 617 855
2040; e-mail: dlee@mclean.harvard.edu
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.12.021

Z. Ma et al. / Bioorg. Med. Chem. 16 (2008) 3218–3223
3219
As part of our ongoing investigation of alternative ther-
2. Results and discussion
apies for substance addiction,9 we initiated a compre-
hensive fractionation study guided by opioid receptor
binding activity in an attempt to find new opioid recep-
tor agonists or antagonists from N. forbesii Boiss (Api-
aceae). The roots and rhizomes of N. forbessi have
been used as a diaphoretic, an antifebrile, and an ano-
dyne, and are officially listed in the Chinese Pharmaco-
poeia.10–12 The major active constituents of this herb are
coumarins, volatile oil, and organic acid.12 Pharmaco-
logical studies demonstrated that coumarins including
isoimperatorin, notopterol, and bergapten possess anti-
inflammatory, analgesic, anti-cancer, and anti-coagulant
activities.13 Herein we report the isolation and charac-
terization of a new coumarin glycoside (4) and a new
phenethyl vanillate (11) together with 17 known com-
pounds (1–3, 5–10, 12–18, and sucrose), and their opioid
and dopamine receptor binding activities.
The dried roots and rhizomes (400 g) of N. forbesii were
sequentially extracted with hexane, ethyl acetate, ace-
tone, methanol, and water. In our initial biological study
as shown in Table 1, the hexane and acetone extracts
showed potent binding activity to l, d, and j opioid
receptors and the ethyl acetate extract showed moderate
binding activity to d and j opioid receptors, while the
methanol extract only had moderate binding activity
to d opioid receptor.
The hexane, ethyl acetate, acetone, and methanol ex-
tracts were chromatographed on silica gel columns to
give a new coumarin glycoside (4) and a new phenethyl
vanillate (11), together with 17 known compounds, div-
ersoside (1),14 anisocoumarin H (2),15 7-[(E)-70-hydroxy-
30,70-dimethylocta-20,50-dienyloxy]-coumarin
(3),16

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Z. Ma et al. / Bioorg. Med. Chem. 16 (2008) 3218–3223
Table 1. Binding activities of crude extracts for opioid receptors
Sample ID
Concentration (mg/ml) [3H]DIP rMOR (% of control) [3H]DIP mDOR (% of control) [3H]DIP hKOR (% of control)
Hexane extract 50
AcOEt extract 50
Acetone extract 50
ꢁ5
1
ꢁ1.8 0.2
ꢁ0.9 1.1
39 15
15 12
56 35
10 10
34 18
5
4
MeOH extract
Water extract
50
50
61
NA
2
27
NA
3
53
NA
4
NA, no activity.
notopterol (5),17 notoptol (6),18 bergapten (7),19 isoim-
peratorin (8),20 nodakenin (9),21 8-geranyl-5-methoxyp-
soralen (10),22 p-hydroxyphenethyl anisate (12),23
phenethyl trans-ferulate (13),24 p-hydroxyphenethyl
trans-ferulate (14),25 coniferyl ferulate (15),26 pterostil-
bene (16),27 chrysoeriol 7-rutinoside (17),28 falcarindiol
(18),29 and sucrose. The known compounds were identi-
fied by comparison with their published data or stan-
dard compounds.
23
D
Compound 4 was isolated as white solid with ½aꢀ ꢁ3.3ꢁ
(c 0.12, MeOH). Its molecular formula was determined
to be C27H34O11 by HR ESI-MS. The ESI mass spec-
trum of 4 showed adduct molecular ion peaks at m/z
552 [M+NH4]+ and 535 [M+H]+, and a fragment at
m/z 373 [Mꢁ162+H]+ representing [aglycone+H]+. The
1H NMR spectrum revealed the presence of furancoum-
1
arin, O- geranyl, and monosaccharide moieties. The H
NMR data of furancoumarin system were closely simi-
lar to those of 5, 6, 7, and 8, which included two dou-
blets at d 6.30 and 8.27 (J = 9.6 Hz) attributed to the
pyran ring protons H-3 and H-4, two other doublets
at d 7.19 and 7.80 (J = 2.4 Hz) corresponding to the fur-
an ring protons H-10 and H-9, and one olefinic proton
1
at d 7.20 (s) for H-8. The H and 13C NMR data of
Figure 1. Selected HMBC correlations of 4 and 11.
O-geranyl and monosaccharide moieties were almost
1
super-imposable on those of 1. Assignments of the H
and 13C signals of 4 by 2D-NMR spectra showed that
4 was an analogue of 60,70-dihydroxybergamottin,30 in
which the glucose unit was attached at C-60. This was
further evidenced by 13C–1H long-range correlation in
the HMBC spectrum (Fig. 1), in which the correlations
[H-100 (d 4.27)/C-60 (d 89.5) and H-60 (d 3.39)/C-100 (d
105.4)] were clearly established. In addition, the HMBC
correlation between H-10 (d 5.06) and C-5 (d 150.3) con-
firmed that the O-geranyl moiety was linked to C-5. On
the basis of these data, the structure of 4 was elucidated
as 60-O-b-D-glucosyl-70-hydroxybergamottin.
revealed the presence of 4-hydroxy-3-methoxybenzoic
acid (vanillic acid) and 4-methoxyphenethyl alcohol
moieties in the molecule. The structure of 11 was thus
determined as 40-methoxyphenethyl vanillate. The pro-
posed structure was further confirmed by synthesis of
11 from vanillic acid and 4-methoxyphenethyl alcohol
as shown in Scheme 1.
The affinities of the isolated compounds for the KOR,
MOR, and DOR were determined by competitive inhi-
bition of [3H]diprenorphine binding to the human
KOR (hKOR), the rat MOR (rMOR), and the mouse
DOR (mDOR), stably expressed in Chinese hamster
ovary (CHO) cells as reported previously.31 All com-
pounds were initially screened at 10 lM. Only com-
pounds anisocoumarin H (2) and falcarindiol (18) at
10 lM inhibited [3H]diprenorphine binding to the opi-
oid receptors by more than 50%. Binding experiments
were then carried out with a range of concentrations
of the two compounds and the Ki value, a measure of
binding affinity, of each compound for the rMOR,
mDOR, and hKOR was determined (Table 2). Com-
pound 18 showed weak affinities to rMOR
(Ki = 1125 nM), mDOR (Ki = 1096 nM), and hKOR
(Ki = 2515 nM), while 2 exhibited weaker affinity for
Compound 11 was isolated as a colorless resin. Its
molecular formula was established as C17H18O5 by
1
HR ESI-MS. The H NMR spectrum displayed the sig-
nals due to a set of ABX type aromatic protons at d 6.93
(1H, d, J = 8.1 Hz), 7.51 (1H, d, J = 2.1 Hz), and 7.61
(1H, dd, J = 2.1 and 8.1 Hz), a set of AB type aromatic
protons at d 6.86 and 7.20 (each 2H, d, J = 8.7 Hz), two
methoxyl protons at d 3.79 and 3.92 (each 3H, s), and
aliphatic protons due to –CH2CH2O– moiety at d 3.00
and 4.46 (each 2H, J = 7.2 Hz). The 13C NMR spectral
data of 11 were analyzed and 13C–1H connectivities in
the molecule were confirmed with aid of the HMQC
and HMBC spectra (Fig. 1). The above NMR data

Z. Ma et al. / Bioorg. Med. Chem. 16 (2008) 3218–3223
3221
3'
6'
2'
4'
OMe
O
O
2
8'
1'
5'
1
OMe
MeO
HO
MeO
7
DCC,DAMP
CH2Cl2, rt
O
3
OH
7'
6
4
HO
HO
5
Scheme 1. Synthesis of 11.
Table 2. Ki values of the isolated compounds for opioid and dopamine receptors
Compound
Ki (nM) for [3H]DIP rMOR
Ki (nM) for [3H]DIP mDOR
Ki (nM) for [3H]DIP hKOR
Ki (nM) for [3H]SCH rD1R
2
>10,000
>10,000
1125 51
>10,000
>10,000
1096 35
2600 450
>10,000
2515 54
>10,000
1422 68
5
18
192
6
the hKOR (Ki = 2600 nM). Furthermore, the isolated
compounds (1–18) were screened for inhibition of bind-
ing to rat DA 1 receptors. Compounds 5 and18 inhibited
[3H]SCH binding to rat D1 receptors by more than 50%
at a concentration of 10 lM. The binding affinities of 5
and 18 were also studied. Compound 5 exhibited low
affinity (Ki = 1422 nM), while 18 showed moderate affin-
ity to D1 receptor (Ki = 192 nM).
for column chromatography. TLC was performed on
precoated silica gel 60 F254 plates (Merck, Germany).
3.2. Plant material
The dried roots and rhizomes of N. forbesii were pur-
chased in April, 2006 from downtown of Boston, MA.
Its botanical identification was confirmed by Dr. S.L.
Chen at IMPLAD in China. A voucher specimen
(MCL-2006-01) has been deposited in the Bio-Organic
and Natural Products Laboratory, McLean Hospital,
Belmont, MA.
Falcarindiol (18) was isolated with a yield of 1.3% (5.2 g
from 400 g raw material), and it should be the principal
constituent for the binding activities to l, d, and j opi-
oid receptors and D1 receptor. Compound 18 belongs to
aliphatic C17-polyacetylenes, and is widely distributed
in the Apiaceae and Araliaceae,32,33 and exhibited signif-
icant cytotoxic, antimicrobial, antibacterial, antifungal,
antimutagenic, antiproliferative, and hepatoprotective
activities.34–40 Recently, Kim et al. reported that 18
dose-dependently inhibited the iNOS-mediated nitric
oxide (NO) production in LPS-activated BV-2 and
microglia, and inhibited the NO-mediated neuronal
death by reducing excessive NO production in the
LPS-treated organotypic hippocampal cultures.41 Kim’s
results suggest that 18 is a useful inhibitor for NO-med-
iated neuronal death.41 In addition, 18 can elevate the
neurotransmitter GABA levels in the central nervous
system by an inhibitory action on the GABA degrada-
tive enzyme GABA transaminase.42 Furthermore, it
has been reported compounds 14 and 18 exhibited inhib-
itory effects on [3H]LSD binding to the serotonin (5-
HT7) receptors.43
3.3. Extraction and isolation
The dried roots and rhizomes of N. forbesii (400 g) were
powdered and extracted with sonication three times with
hexane (1.6 L each time) at room temperature (25 ꢁC)
for 30 min, and the hexane solution was evaporated in
vacuo to give a residue (21 g). The ethyl acetate, ace-
tone, methanol, and water extracts (32, 7, 30, and
26 g) were obtained by the same procedure. The hexane
extract (20 g) was chromatographed over silica gel
(200 g) using hexane with increasing amounts of ethyl
acetate (20:1, 10:1, 5:1, 2:1, and 1:1) to give five fractions
A–E. Fraction B was further purified by silica gel col-
umn with a gradient of methylene chloride and ethyl
acetate to afford 8 (430 mg) and 18 (3.0 g). Fraction C
was chromatographed over silica gel column with a gra-
dient of methylene chloride and ethyl acetate to afford
10 (3 mg), 11 (3 mg), 13 (140 mg), and 16 (2 mg). Frac-
tion D was purified by silica gel column with a gradient
of hexane and ethyl acetate to afford 2 (15 mg), 3
(10 mg), 5 (30 mg), 6 (10 mg), and 12 (330 mg). Fraction
E was chromatographed over silica gel column with a
gradient of methylene chloride and ethyl acetate to
afford 7 (3 mg). The ethyl acetate extract (30 g) was
separated by normal phase silica gel column chromatog-
raphy to obtain 8 (450 mg), 9 (15 mg), 12 (4.5 g), 14
(3 mg), 15 (5 mg), and 18 (2.0 g). The acetone extract
(6 g) was separated by a combination of normal phase
silica gel column chromatography and HPLC (ODS col-
umn, 10 · 250 mm, 60% methanol, 2 ml/min) to obtain 1
(160 mg), 4 (5 mg), 8 (10 mg), 9 (80 mg), 12 (100 mg),
and 18 (250 mg). In a similar manner, 1 (50 mg), 9
(20 mg), 17 (15 mg), and sucrose (8.0 g) were isolated
from the methanol extract (28 g).
3. Experimental
3.1. General experimental procedures
Optical rotations were measured with an AUTOPOL III
digital polarimeter. NMR spectra were recorded on a
Varian VXR300 spectrometer with TMS as the internal
standard. EI-MS spectra were obtained on a HP5972
Series Mass spectrometer. ESI-TOFMS spectra were
measured on a Micromass Plateform II mass spectrom-
eter. HPLC was carried out on a Varian Prostar 210 Sol-
vent Delivery Module (California, USA) equipped with
a Varian ProStar 320 UV/Vis Detector at a wavelength
of 254 nm. Silica Gel (Fisher Scientific, USA) was used

3222
Z. Ma et al. / Bioorg. Med. Chem. 16 (2008) 3218–3223
3.4. 60-O-b-D-Glucosyl-70-hydroxybergamottin (4)
displacement of [3H]diprenorphine at 10 lM were fur-
ther tested for the affinity (Ki). The Ki value of each
compound was calculated from the competitive inhibi-
tion curves using the Prism 3.0 program (GraphPad
Software Inc., San Diego, CA).
23
D
1
White powder; ½aꢀ ꢁ3.3ꢁ (c 0.12, MeOH); H NMR
data (300 MHz, CD3OD): d 8.27 (1H, d, J = 9.6 Hz,
H-4), 7.80 (1H, d, J = 2.4 Hz, H-9), 7.20 (1H, s, H-8),
7.19 (1H, d, J = 2.4 Hz, H-10), 6.30 (1H, d, J = 9.6 Hz,
H-3), 5.66 (1H, t, J = 6.6 Hz, H-20), 5.06 (1H, d,
J = 6.6 Hz, H-10), 4.27 (1H, d, J = 7.8 Hz, H-100), 3.84
(1H, dd, J = 2.4 and 12.0 Hz, H-600), 3.64 (1H, dd,
J = 5.4 and 12.0 Hz, H-600), 3.39 (1H, dd, J = 2.4 and
9.6 Hz, H-60), 3.16–3.33 (4H, m, H-200, H-300, H-400 and
H-500), 2.45 (1H, m, H-40), 2.27 (1H, m, H-40), 1.70
(1H, s, H-100), 1.48-1.70 (2H, m, H-50), 1.45 (1H, s, H-
80), and 1.10 (1H, s, H-90); 13C NMR data (75 MHz,
CD3OD): d 163.2 (C-2), 159.7 (C-7), 153.8 (C-8a),
150.3 (C-5), 146.9 (C-9), 144.4 (C-30), 141.5 (C-4),
121.0 (C-20), 115.9 (C-6), 113.1 (C-3), 108.8 (C-4a),
106.3 (C-10), 105.4 (C-100), 94.8 (C-8), 89.5 (C-60), 78.1
(C-300), 78.0 (C-500), 75.3 (C-200), 73.4 (C-70), 71.4 (C-
400), 70.7 (C-10), 62.5 (C-600), 36.8 (C-40), 31.0 (C-50),
26.5 (C-90), 24.5 (C-80), 16.6 (C-100); ESI-MS m/z: 552
[M+NH4]+, 535 [M+H]+, 373 [Mꢁ162+H]+; HR ESI-
MS: m/z 552.2452, [(M+NH4)+, calcd for C27H38O11N
552.2445].
3.8. Competitive inhibition of [3H]SCH23390 binding to
dopamine receptor
Chinese hamster ovary cells (CHO) stably transfected
with HA-tagged rat D1 dopamine receptor (rD1R) were
grown in 100-mm culture dishes in Dulbecco’s modified
Eagle’s medium F12 HAM supplemented with 10% fetal
calf serum, 0.1 mg/ml hygromycin B, 100 U/ml penicil-
lin, and 100 lg/ml streptomycin in a humidified atmo-
sphere consisting of 5% CO2 and 95% air at 37 ꢁC.
Membranes were prepared from the CHO cells stably
transfected with rD1R as described previously.44 Bind-
ing to membranes prepared from CHO cells stably
transfected with the rD1R was performed with
[3H]SCH23390 (0.2 nM) in 50 mM Tris–HCl buffer con-
taining 1 mM EGTA (pH 7.4) (TE buffer) at room tem-
perature for 1 h in duplicate. Nonspecific binding was
defined as binding in the presence of Fluphenazine
(10 lM). The purified compounds showing more than
50% displacement of [3H]SCH23390 at 10 lM were fur-
ther tested for the affinity (Ki) by using GRAPHPAD
PRISM.
3.5. 40-Methoxyphenethyl vanillate (11)
Colorless resin; 1H NMR data (300 MHz, CDCl3: d 7.61
(1H, dd, J = 2.1 and 8.1 Hz, H-6), 7.51 (1H, d,
J = 2.1 Hz, H-2), 7.20 (2H, d, J = 8.7 Hz, H-20 and H-
60), 6.93 (1H, d, J = 8.1 Hz, H-5), 6.86 (2H, d,
J = 8.7 Hz, H-30 and H-50), 4.46 (2H, t, J = 7.2 Hz, H-
80), 3.92 (3H, s, C-4-OMe), 3.79 (3H, s, C-40-OMe),
3.00 (2H, t, J = 7.2 Hz, H-80); 13C NMR data
(75 MHz, CDCl3): d 166.3 (C-7), 158.3 (C-40), 153.8
(C-8a), 150.0 (C-4), 146.1 (C-3), 130.0 (C-10), 129.9 (C-
20 and C-60), 124.1 (C-6), 122.4 (C-1), 114.0 (C-5),
113.9 (C-30 and C-50), 111.7 (C-2), 65.5 (C-80g286),
56.0 (C-4-OMe), 55.2 (C-40-OMe), and 34.4 (C-70);
ESI-MS m/z: 320 [M+NH4]+, 303 [M+H]+; HR ESI-
MS: m/z 320.1495 [(M+NH4)+, calcd for C17H22O5N
320.1498].
Acknowledgments
The authors thank Department of Chemistry and
Chemical Biology, Harvard University, for MS determi-
nation, Dr. S.L. Chen for botanical identification, and
Dr. Ruicao Shen for help with optical rotation measure-
ments. This work was supported by research grant (P01-
AT-002038-04, NCCAM/NIAAA) to D.Y.L.
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