ARTICLE IN PRESS

Phytomedicine 17 (2010) 19–22

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Phytomedicine
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Tea catechins’ affinity for human cannabinoid receptors

G. Korte a,n, A. Dreiseitel a, P. Schreier b, A. Oehme b, S. Locher b, S. Geiger c, J. Heilmann c, P.G. Sand a
a
Department of Psychiatry, University of Regensburg, Franz-Josef-Strauss-Allee 11, H4 R97 93053 Regensburg, Germany
b
Chair of Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
c
Chair of Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Universitaetsstrasse 31, 93053 Regensburg, Germany

a r t i c l e in fo abstract

Among the many known health benefits of tea catechins count anti-inflammatory and neuroprotective
Keywords: activities, as well as effects on the regulation of food intake. Here we address cannabimimetic
Camellia sinensis bioactivity of catechin derivatives occurring in tea leaves as a possible cellular effector of these
Catechins functionalities. Competitive radioligand binding assays using recombinant human cannabinoid
Epigallocatechin-3-O-gallate receptors expressed in Chem-1 and CHO cells identified (–)-epigallocatechin-3-O-gallate, EGCG
Cannabinoid receptor (Ki = 33.6 mM), (–)-epigallocatechin, EGC (Ki =35.7 mM), and (–)-epicatechin-3-O-gallate, ECG (Ki =47.3
Neuroprotection mM) as ligands with moderate affinity for type 1 cannabinoid receptors, CB1. Binding to CB2 was weaker
with inhibition constants exceeding 50 mM for EGC and ECG. The epimers (+)-catechin and (–)-
epicatechin exhibited negligible affinities for both CB1 and CB2. It can be concluded that central nervous
cannabinoid receptors may be targeted by selected tea catechins but signaling via peripheral type
receptors is less likely to play a major role in vivo.
& 2009 Elsevier GmbH. All rights reserved.

Introduction
Catechins are the most abundant polyphenols in the leaves of
tea (Camellia sinensis (L.) O. KUNZE) but are also found in many
fruits and in some legumes, e.g. in cocoa beans (Arts et al. 2000).
While the average daily catechin intake in Western diets has
been estimated at 50 mg (Arts et al. 2001), ‘‘Mediterranean’’ type
diets contain twice as much catechins (Auger et al. 2004)
and have become known for their health-promoting effects
(Ruidavets et al. 2000). These include a reduced incidence of
stroke (Keli et al. 1996; Tanabe et al. 2008), the slowing of age-
related cognitive decline (Kuriyama et al. 2006), and protection
against obesity (Kao et al. 2000; Murase et al. 2006). Animal
studies suggest an additional role of catechins or catechin
oligomers in nociception (Rylski et al. 1979; DalBó et al. 2005;
Dias et al. 2007; Tang et al. 2007) and in imparting resistance to
stress (Abbas and Wink 2009). At the cellular level, catechins
induce anti-inflammatory (Tedeschi et al. 2002) and antioxidant
activities (Higdon and Frei 2003) but there is some disagreement
regarding the signaling pathways that mediate the above
functionalities (Cooper et al. 2005). Thus GABAergic, glutamater-
gic, monoamine and NO systems (Adachi et al. 2006; Chou et al.
2007; Rocha et al. 2007; Kim et al. 2007) have previously been
proposed as catechin effectors, among others. Only recently, lipid
n
Corresponding author. Tel.: +49 941 944 8955; fax: + 49 941 944 8956.
E-mail address: gabriele.korte@klinik.uni-regensburg.de (G. Korte).
rafts (Patra et al. 2008) and plasma membrane binding sites
(Bastianetto et al. 2009) have been implicated as molecular
targets. We therefore hypothesized that catechin pharmacology
could involve further sites of action and tested cannabimimetic
activities.
Two human cannabinoid receptors (CB) have so far been
identified. Of these, CB1 is expressed primarily in the central
nervous system (CNS) (Matsuda et al. 1990) where it acts through
lipid rafts (Bari et al. 2005). CB1 plays a pivotal role in
neuroprotection (Galve-Roperh et al. 2008) and food intake
(Richard et al. 2009). CB2, in contrast, is expressed predominantly
outside the CNS (Munro et al. 1993) and is most prevalent in cells
of the immune system (Lynn and Herkenham 1994). CB ligands
comprise natural analgesics (Walker and Hohmann 2005) of
which cannabinoids have been extensively investigated (Woelkart
et al. 2008). The present study examines in vitro affinities of (–)-
epigallocatechin-3-O-gallate (EGCG), (–)-epicatechin-3-O-gallate
(ECG), (–)-epigallocatechin EGC, (–)-epicatechin, and ( + )-catechin
(Fig. 1) for human CB1 and CB2.
Materials and methods
Membrane preparations of recombinant human cannabinoid
receptors 1 (Chem-1 cells) and 2 (CHO cells) were purchased from
Millipore (Schwalbach, Germany), catechin derivatives were
obtained from Extrasynthese (Genay, France), [3H]-CP55940 was
purchased from PerkinElmer (Boston, MA, USA) and unlabeled

0944-7113/$ - see front matter & 2009 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2009.10.001
 ARTICLE IN PRESS
20 G. Korte et al. / Phytomedicine 17 (2010) 19–22
Fig. 1. Chemical structures of catechin derivatives under study.
CP55940 was purchased from Sigma-Aldrich (Schnelldorf,
Germany). CB1 (Kd =29.4 nM) and CB2 (Kd = 12.0 nM) saturation
characteristics were determined with CP55940 concentrations of
1–12.5 nM (six concentration steps), and 1–20 nM (five concen-
tration steps), respectively, using 10 mg (CB1) or 2.5 mg (CB2) of
synaptosomes. For radioligand receptor assays, 100 ml of mem-
brane preparations were added to 80 ml of assay buffer (50 mM
Hepes, 0.5% BSA, pH 7.4), 10 ml of test compounds dissolved in
DMSO and 10 ml of [3H]-CP55940, followed by an incubation of
90 min at room temperature in microtiter plates (final concentra-
tions per well: DMSO 5% (v/v), ethanol 0.28% (v/v), radioligand
12.5 nM or 15 nM, CB1/2 synaptosomes 10 mg). Specific binding
for each compound at each concentration was defined as total
binding minus binding in the presence of unlabeled CP55940
(10 mM), and was determined for each concentration of [3H]-
CP55940. Reactions were terminated by filtration through a GF/C
Filtermat A (PerkinElmer, Boston, MA, USA) using a 96-well
Inotech cell harvester (Dietikon, Switzerland) and by subsequent
washing of filters with distilled water. Prior to filtration, filter
mats were first soaked in buffer containing 0.33% polyethylenei-
mine for 1 h, and were washed with 50 mM Hepes (0.5% BSA, pH
7.4). After filtration, filters were dried at 60 1C for 60 min and were
then transferred to scintillation vials. 4 ml of Rotiszint eco plus
scintillation cocktail (Roth, Karlsruhe, Germany) were added to
each vial and radioactivity was determined in a WinSpectral 1414
liquid scintillation counter (PerkinElmer Wallac GmbH, Freiburg,
Germany). All experiments were performed in triplicate using
seven concentration steps per compound investigated. Mean
values 7SD were obtained for each step and served for normal-
ization and curve-fitting. Competitive radioligand displacement
was evaluated by nonlinear regression analysis (GraphPad Prism
V2.01, GraphPad Software, LaJolla, CA, USA). Ki values were
derived from the equation by Cheng and Prusoff (1973):
EC50
Ki ¼
1 þ ½ligand
Kd
Results and discussion
Dose-dependent binding to CB1 and CB2 was noted for all
compounds under study. Overall, Ki values differed by several
orders of magnitude ranging from 33.6 mM for EGCG to over
2.5 mM for ( + )-catechin and (–)-epicatechin with regard to CB1.
Receptor affinities for CB1 were generally stronger than the
respective affinities for CB2 (Table 1). While CB1 inhibition
constants below 50 mM were achieved by EGCG, EGC and ECG,
only EGCG exhibited a similar Ki for CB2. CB2 half-maximal
inhibition could not be determined for ( +)-catechin and (–)-
epicatechin as values of these flavonoids fell outside the upper
detection limit of the displacement assay. The present data
suggest that selected tea catechins feature moderate affinity for
central type CB whereas binding to peripheral type CB is less
prominent (Fig. 2). Thus cannabimimetic activities may contribute
to CNS effects of green tea extracts including the mitigation of
pain (Singal et al. 2005; Sattayasai et al. 2008), complementing a
COX-2 inhibitory role (Kaur et al. 2005) and known opioid
receptor functionalities of catechins (Capasso et al. 1998; Katavic
et al. 2007). In addition, CB1 ligands EGCG, EGC and ECG in green
tea may modulate food intake (Auvichayapat et al. 2008; Bose et
al. 2008). However, a cautionary note is warranted in that the
magnitude of anti-obesity effects is not undisputed (Diepvens et
al. 2005) and both anti-nociceptive and anti-obesity activities
imply agonistic modulation of CB1 which is unproven by our
experiments. Observational studies on neuroprotection by green
tea polyphenols (Kakuda 2002; Pan et al. 2003) lend some support
to putative CB1 agonistic effects but will require further
confirmation, e.g. by monitoring intracellular Ca2 + levels or
steady state [32P]-GTPase activity. As for anti-allergic properties
of catechin-enriched preparations (Maeda-Yamamoto et al. 2007),
these are less likely to result from binding to CB in view of mostly
poor CB2 Ki values.
With respect to both CB1 and CB2, negligible bioactivities were
noted for ungallated catechins. In previous reports, the galloyl
moiety has been associated with catechins’ radical scavenging
qualities (Nanjo et al. 1996; Kinjo et al. 2002; Wolfe and Liu 2008),
with inhibition of COX-2 (Hou et al. 2007), protein tyrosine
phosphatase (Okamoto et al. 2003), pancreatic lipase (Ikeda et al.
2005) and fatty acid synthase (Wang et al. 2003), but not with
enhanced GABAergic neurotransmission (Adachi et al. 2007). The
30 , 40 , 50 -trihydroxyl substitution in the catechin B-ring, in turn,
which has been implicated in antioxidant, apoptosis-inducing and
beta secretase-inhibiting activity of catechins (Furuno et al. 2002;
Saeki et al. 2000; Jeon et al. 2003) did not appear to contribute to
CB binding. More detailed structure-activity investigations are
invited to address the interplay of galloyl and pyrogallol moieties,
 ARTICLE IN PRESS
G. Korte et al. / Phytomedicine 17 (2010) 19–22 21

Table 1
Affinities of catechin derivatives and CP55940 for human cannabinoid receptors 1 and 2 as determined in competition binding assays on membrane preparations of
recombinant receptors. [3H]-CP55940 was used as radiolabeled ligand. All experiments were performed in triplicate.

Compound Ki (CB1) in lM 95% CI Ki (CB2) in lM 95% CI

(-)-epigallocatechin-3-O-gallate (EGCG) 33.6 17.2 - 65.7 42.8 17.9 - 101.0

(-)-epicatechin-3-O-gallate (ECG) 47.3 16.7 - 133.8 95.6 23.0 - 397.4
(-)-epigallocatechin (EGC) 35.7 3.5 - 368.2 361.3 0.5 - 24,000
( +)-catechin 42,500.0 n.d. n.d. n.d.
(-)-epicatechin 42,500.0 n.d. n.d. n.d.
CP55940 0.028 0.008 - .095 0.025 0.015 - .039

n.d.= not determined.

of ungallated flavan-3-ols (Warden et al. 2001; Henning et al.

CB1
2008), signal strength may be amplified in vivo by non-receptor
% specific [3H]-CP55940

100 related mechanisms, e.g. by inhibition of fatty acid amide

hydrolase or COX-2 (Jhaveri et al. 2008). Future studies will need
to address the impact of these confounders to allow for a balanced
binding

view of putative health benefits that may be mediated by CB.

50
CP55940
EGCG
EGC Acknowledgement
ECG
0
This work was supported by grant #0313848C from the
-10 -9 -8 -7 -6 -5 -4 -3 German Federal Ministry of Education, Science, Research and
log (drug) [M] Technology.

CB2
% specific [3H]-CP55940

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Fig. 2. Displacement curves for selected CB1 and CB2 ligands in competition
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