S60

Cannabinoids: The Separation of Central from

Peripheral Effects on a Structural Basis
Fredi. Evans
Department of Pharmacognosy. The School of Pharmacy, University of London, 29—39 Brunswick Square,
London WC1N lAX, U.K.

moved from the Merck Index in 1950 and even from the In-
Abstract dian Pharmacopoeia in 1966 when the social controversy in
Western countries was probably reaching its height. In the
A brief history of the therapeutic uses and U. K. the possession of cannabis is controlled by the 'Misuse
legal problems of cannabis as well as the component can- of Drugs Act' of 1971 and it is not available for prescription
nabinoids is given. This is followed by a discussion of or for experimental purposes except on a Home Office Li-
drug development from 1-tetrahydrocannabinol and its cence. Under this Act the pure cannabinoids are classified
synthetic analogues. The controversy of whether the as class A drugs equivalent to heroin whilst herbal cannabis
pharmacological effects are of central or peripheral ori- is classified as class B. The criminal penalties are consider-
gin is included. Then, the potentials for the development ably less for possession of class B drugs. The difficulties

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of new drugs based on the cannabinoid structure for the which have to be overcome for research into the properties
treatment of pain, inflammation, and related conditions of cannabis have in recent years led to a decline in medical
are outlined. It is concluded that the central activity of as opposed to social science publications in this area.
cannabinoids is confirmed and that the presence of a C-5 Nevertheless, this decline in research is surprising consid-
hydroxy group confers potent peripheral activity. ering the many well known medical properties of the herb.

Keywords - The medicinal properties of cannabis were

first recognised in China about 2000 years ago (1). The drug
Cannabis, Cannabis sativa, drug develop- was widely used in India and Middle Eastern countries (2)
ment, hallucinogenic activity, central effects, peripheral and was introduced into Europe by the Irish surgeon
effects, structure-activity relationships. O'Shaughnessy in 1842. Preparations of cannabis were
used for a variety of ailments including the relief of pain,
Abbreviations and Symbols muscle spasms, convulsions, epilepsy, asthma, rheuma-
tism, and menstrual cramp (3, 4). Cannabis however, like
CBD: cannabidiol other herbal preparations, proved to be unreliable in its po-
CBG: cannabigerol tency due to a lack of standardisation procedures at that
CBN: cannabinol time and there was uncertainty as to the optimum dosage
CNS: central nervous system regime. It was not surprising that the discovery of more reli-
TOP: intraocular pressure able synthetic drugs led to the eventual disuse of crude her-
OL: olivetol bal extracts of cannabis in Western medicine. A renewal of
PAF: platelet-activating factor interest in the medical properties only occurred following
PBQ: phenylbenzoquinone the structure elucidation of the cannabinoids as the active
PG: prostaglandin principles of the herb and the resin in the 1960's.
PKC: protein kinase C
THC: A 1-tetrahydrocannabinol The Cannabinoids
TPA: tetradecanoylphorbol acetate
The principle chemical components of can-
nabis are the cannabinoids (Fig. 1). The first of these com-
pounds to be isolated was the artifact cannabinol (CBN) (5)
followed shortly afterwards by the true natural product
Introduction cannabidiol (CBD) (6). It soon became obvious that these
substances did not represent the major portion of the
Cannabis is one of the more unfortunate of biological activity of cannabis extracts and the isolation in a
the herbal preparations used in medicine over the last 2000 pure form of'-tetrahydrodrocannabinol (THC), the major
years. Its social abuse, due to its central hallucinogenic ac- hallucinogenic principle, awaited the development of more
tions, has overshadowed its potential use as a medicine. sensitive chromatographic methods in the 1960's (7). To-
Moral objections and political involvement have contri- gether with spectroscopic methods including NMR, struc-
buted to its rejection as a medicine and it was removed from tures were elucidated and a large number of closely related
the British Pharmacopoeia as early as 1932 and from the cannabinoid compounds discovered. Reviews on the
United States Pharmacopoeia a decade later. It was re- chemistry of the many cannabinoid derivatives have previ-
Separation of Centralfrom Peripheral Effects on a Structural Basis Planta Med. 57 (1991), Supplement Issue 1 1991 S61

ously been published [for example (8—10)1. The numbering in mice but using the cataleptic test, the effects of THC were
system used in Fig. 1 is reproduced from (8) and treats the inhibited by aspirin, a cyclooxygenase inhibitor (26), and
cannabinoids as aryl-substituted meroterpenes. Thus for reversed by the administration of PG's and these authors
the first time the pharmacologist and physician could be suggested the involvement of PG's in some of the properties
provided with pure materials of proven structure for biolog- of the cannabinoids.
ical investigations. The vast majority ofthese investigations
involved THC for which a number of new applications were Despite the contradictions concerning the
found and synthetic programmes based upon that structure mechanism of action of THC, certain structure-activity rela-
have led to the marketing of new drugs. tions were tentatively assembled on a qualitative rather
than a quantitative basis (27— 29) and these were devoted to
Drug Development from THC the central hallucinogenic effects of THC or from animal
models believed to correlate with hallucinicity in man. The
The pharmacological and therapeutic ef- most significant of these observations were that firstly a
fects of THC have been reviewed (11—13) and it was these tricyclic structure is required for activity, the aromatic ring
results which led to the development of synthetic analogues is necessary for high activity, removal of the phenolic group
related to that hallucinogenic cannabinoid. Cannabis or its of the benzene ring (C-5') reduces or in some cases
active principle THC were used in the treatment of diverse abolishes activity, that the double bond in the terpene ring
disease conditions including glaucoma, as an anti-convul- is not a requirement for activity, and that the C-3' phenolic
sant, to reduce body temperature, as an anti-emetic, an group is essential for central actions. Synthetic derivatives
hypotensive agent, in the treatment of muscle spasticity,
and as a sedative (14). The drug was also used for the relief
of pain and for the treatment of inflammatory and related
OH3 OH3
conditions (15).

fl')

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One of the major problems with the THC
molecule has been the contradictions concerning its
mechanism of action. Some of the effects of THC could be H COj>iCH2 )—CH3 3
peripherally mediated whilst others appeared to be of cen- R
tral origin. This problem can be illustrated in the case of the R H, n 4: ,O,1-tetrahydrocannabinct (THCI 5x6-tetrahydrocannabinol
use of THC in glaucoma. Hepler and Frank (16) observed H = COOH, n 6: tetrahydrocannabinolic acid
that the smoking of marihuana (0.9—1.5% of THC) reduced H H, n 2: tetrahydrocannabivarot
intraocular pressure (lOP) after 30—40 mm by up to 45%. In H COOH, n 2: tetrahydrocannabivarolic acid
pharmacological experiments the effects of THC were H H, n 0: tetrahydrocannaborcinot
shown to be longer lasting than the contempory eye drop
pilocarpine (17). However, in the case of THC the other eye OH3
was also affected even when THC preparations were
applied to one eye only, indicating systemic adsorption of
the drug. The effects of THC on lOP were considered to be
)oH OH3

mediated (18) via the CNS when it was shown that the effect
of the drug was decreased in the denervated eye. In con-
trast, the case for peripheral involvement has also been
H3OlH3O
R
H
3O' OH OH2)rcO H3

proposed as a mechanism of action. It is known that high H H, n 6: cannabinot ICBH) H H, n = 4: cannabidiot ceoi
doses of prostaglandins (PG's) cause a rise in lOP (19, 20) H = COOH, n 4: cannabinolic acid H = cOOH, n 6: cannabidiolic acid
and the demonstration that THC blocked the release of R = H, n 2: cannabivarol H = H, n 2: cannabidvarot
arachidonic acid-induced increase in TOP in the rabbit H COOH, n 2: cannabivarolic acid H = COOH, n 2: cannabidvarotic acid
whilst the administration of PGE2 reversed this effect (21) H H, n 0: cannaborcinot H = H, n = 0: cannabidiorcinot

strongly indicates a peripheral involvement in the utility of

THC for the treatment of glaucoma. In addition intraocular OH

H 3O'f)
H30 H3C
fluid dynamics may also be involved. THC reduces fluid pro-
duction in the rabbit eye (22) and this may be due to effects
upon secretory mechanisms such as carbonic anhydrase HO 'iO H2)0— OH3
(23) inhibition. R

H H, n 4: cannabigerot ICBO)
Another interesting example is the use of H = COOH, n 4: cannabigerotic acid
THC in the treatment of anxiety and as a sedative. Clinical H H, n 2: cannabigerovarot
trials have demonstrated that sedation is the most common
effect of THC (24). However, in animal experiments when a Fig. 1 The cannabinoid constituents of Cannabis sativa L. The major
mechanism has been sought both central and peripheral compounds as currently known are illustrated but the cannabis plant
contains in addition a number of compounds including cannabichromen,
modes of action have been proposed. It has been de-
cannabicydol, cannabicitran, flavonoids, and an alkaloid. These substances
monstrated that the effects of THC can be reversed in this are not generally available to the pharmacologist and are not included in this
respect by the administration of RO-151788, a ben- review. An alternative numbering system is also popular in the literature of
zodiazepine receptor antagonist (25), in mice, suggesting the cannabinoids. This system treats the cannabinoids as dibenzopyrans and,
that the natural benzodiazepine receptor in the CNS is in- according to Orombie and Orombie (8), may also be used as opposed to the
volved with this aspect of the effects of THC. However, also numbering system generally used in their original review (8).
S62 Planta Med. 57(1991). Supplement Issue 1 1991 Fred J. Evans

of THC have been developed using these principles as The central effects of a number of can-
guidelines for novel drug production. Amongst the first of nabinoids were recently re-evaluated to confirm the struc-
these compounds were the nitrogen-containing com- ture-activity base line as previously described (40). Iii these
pounds from the group of Pars and others (30) including the experiments the ring test in mice as originally described by
3,4-diaza-THC analogues. Several compounds were used Paton and Pertwee (41) was used. This test is said to be a
clinically, such as BW 146Y, levonanthradol (a nuclear ni- pharmacological model which is a direct correlate with hal-
trogen derivative, Fig. 2) and the most successful of all, lucinogenic actions in man (42) and should provide evi-
nabilone. All of these compounds in one form or another re- dence for the segregation of central effects on a structural
tained the principle of the three-ring structure as being nec- basis. A range of commercially available cannabinoids was
essary for activity. Nabilone is still in use today, it is mar- assessed. These included CBD, CBN, CBG, and the sup-
keted under the trade name of "Cesamet". The drug is man- posed cannabinoid biosynthetic precurser olivetol (OL). The
ufactured by the Lilly company and was introduced for the results confirmed previous structure-activity relationships
treatment of nausea mainly in patients undergoing radia- in that the tricyclic cannabinoid, THC, was shown to be the
tion therapy for cancer (31—33). The compound also has only compound which induced catalepsy in mice (Fig. 3).
some analgesic activity which would be of advantage in THC induced catalepsy at doses of 0.625 mg/kg to 25 mgI
these circumstances. However, the compound is not devoid kg, whilst the other cannabinoids, OL, CBN, CBD, and CBG
of central effects which include drowsiness, dizziness, di- were inactive up to tested doses of 100 mg/kg. Further ex-
vided co-ordination, and low blood pressure (34—36). In
the British National Formulary (BNF 1988), cautions in-
clude a warning that this drug may effect the patients ability
to operate machinery or to drive a car. Clearly there was no
complete separation of central from peripheral activity in 80
these compounds, although certain aspects of the multiple
70
effects of THC may have been selectively enhanced.

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60
Potential Development in the Treatment
of Pain, Inflanunation,, and 50
Related Conditions 0.
40
S
Major problems still exist in the develop- 30
ment of drugs from the canriabinoid structure. The target C

site for drug development has not been identified, there is 5

S
6
20
confusion in the literature concerning the mechanism(s) of 10
action and current structure-activity studies are designed to
lead to compounds retaining central as well as peripheral
0 1 10 100
actions. Nevertheless, there is sufficient traditional evi-
dence in the literature [for a review, see (14)] to suggest that Dose (ing kg)
in the treatment of inflammatory and related conditions Fig. 3 Induction of catalepsy by cannabinoids: percentage catalepsy
cannabis could form the basis for the development of potent following oral administration of THC (•) CBD (0), CBN (•), CBG (0), and
anti-inflammatory agents which retain no central activity olivetol (A). The values are the mean and the vertical lines represent the se.
and the side-effects associated with that action. THC is con- mean where n 7 animals per group.
sidered as the major active substance of cannabis and most
other cannabinoids such as CBD, CBG, and CBN are de-
scribed as non-active due to the absence of the classical
three-ring structure (29). Activities have been claimed for '-I
0
some of these compounds (37—39) in various biological sys- 0
0
tems and one or more of these structures could provide a 00 30(
• TI-IC
new approach to the production of effective drugs. • CBD
04-,
o cn
1' o CBN
-H
4-,
(0

H3
a0
C
H3C—C—O. 0
4-,
(U
'-4
IH
H3C' OH3 -H
4-,
nabilone (evonanthradol (1) 0
—20
20 30 40 50
Fig.2 Synthetic analogues of Q'-THC. Nabilone is quoted as being Concentration (pg/nil)
available as a prescription-only drug in the BNF (1988). It is prescribed for the
treatment of sickness following radiation therapy in cancer patients and is an Fig. 4 Stimulation of phospholipase A2 activity by cannabinoids. Acid
analgesic. release in the absence of drugs: 0.07 0.006zmoI/min.
Separation of Centralfrom PeripheralEffects on a Structural Basis Planta Med. 57(1991). Supplement issue 1 1991 S63

periments using THC with CBN demonstrated that CBN was HO

capable of inhibiting the cataleptic effects of THC. An ex- H
tract of cannabis was also tested, which by GLC analysis
contained THC, CBN, and CBD; this preparation, which
from its THC content alone should have considerable HO OH3
cataleptic effects, was also inactive, as was a prepared mix- H3C OH3
ture of these pure compounds in similar proportions. olivetot (DL) cannabigerot ICBG)

It would seem that illegal samples of can- HO .

nabis should be assessed for the ratios of the major can- H
nabinoids rather than just for their content of THC before
estimates of CNS potency are made. It is also interesting
that CBN is a tricyclic compound (Fig. 1) in which the ter- H3C OH3
penoid side chain is aromatised. CBN is obviously capable
can nabidiot COD) tetrahydrocannabinot liNc)
of crossing the blood/brain barrier and possibly an-
tagonised the effects of THC at its central receptor. Even if
one or both of these compounds are metabolised to hydroxy
ligands this result is of interest in the investigation of the na-
ture of the CNS receptor to THC (43). Several suggestions <Z)?rTJ
have been made in the past [for a review, see (1111 concern- OH3
ing the CNS receptor to THC. One of the more recent obser- H3C OH3
vations has indicated an involvement of the PG's in the cen- cannabinol ICON)
tral effects of THC in that the actions of THC could be an-
tagonised by aspirin, indomethacin, diflunsinal, and Fig. 5 The commercially available cannabinoids. The structures have been

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phenylbutazone (26). Furthermore, Burstein and cowork- drawn based upon olivetol (OL) as the presumed biosynthetic precursor and
ers (44, 45) have proposed that THC interacts with specific numbered accordingly.
sterol binding sites in the plasma membrane causing acti-
vation of phospholipase A2 and hence enhanced cyclo-
oxygenase activity. The most likely target in that case would 100
be a protein kinase which was capable of the phosphoryla-
tion of a lipocortin-like protein. Recently, it has been de- go -
monstrated that THC and several other cannabinoids are
not capable of inhibiting PKC activation except in high go
doses (46). It has also been shown that THC, CBN, CBD, and
CBG have an equipotent stimulation followed by an inhibi- 70 -
tion of the dose-relation curve on phospholipase A2 in a cell t kO -
free assay (Fig. 4) and it is unlikely that that receptor is in- 0

volved directly in the CNS activity of THC (68). 0

50

Although the central hallucinogenic recep- 0

40 -

tor to THC remains unknown, it is now clear that com-

pounds of the cannabinoid structure which exhibit a free C- 30

5 phenolic group rather than the tricyclic structure are de- 20

void of central effects but, in the case of one potential recep-
tor of possible peripheral significance, duplicate the effects 10 -

of THC. This can best be illustrated in Fig. 5 where the struc-

tures of the main cannabinoids have been redrawn in rela-
tion to OL, the biosynthetic precurser. This assumes the im- 1 2 3 4 5
portance of an antioxidant effect at some level in their ac- Log10 Dose pg/kg
tions. The effects of the cannabinoids in several models of Fig. 6 Inhibition of PBQ-induced writhing by pure cannabinoids (±SEM)
inflammation can therefore be re-evaluated. following oral administration of the drug (•—•) CBD; (•—•) THC; (A—A)
08G.
Pain
Table 1 Inhibition of PBQ-induced writhing in the mouse by cannabinoids and
THC was shown to be an analgesic in aspirin. Results are effective dose 50% (mg/kg) and % maximum inhibition in-
human subjects (47) following oral administration of the duced up to a dose of 200 mg/kg with 35 animals per group.
drug and has been used for the relief of pain in cancer pa-
tients (48). Pharmacological investigations of THC in ani- Compound ED50 (mgI kg) Maximum Inhibition (%)

mal models have confirmed this activity. Tests used in- THC 25 100
cluded the hot-plate test (49, 50), the tail flick test (51), PBQ- CBN >25 36
induced writhing (52), the acetic acid abdominal constric- 080 0.042 60
tion test (53, 54), and the tooth pulp test (55). Subsequently ORG 1.26 61
a mechanism of action involving non-opiate central recep- OL 0.63 100
Aspirin 15.0 62
tors has been proposed (49, 56). Sanders and others (53)
S64 Planta Med. 57(1991). Supplement Issue 1 1991 FredJ. Evans

Table 2 The effect of cannabinoids on PAF-induced rabbit platelet aggrega- lungs it has been suggested that inhibition of PG synthesis
tion. PAF (2.9 x 107M) introduced 1 mm after the introduction of the an- could be the mechanism of action; however, in healthy vol-
tagonists. unteers the administration of PG's had no effect upon the in-
Compound ED50 (M x 10-a) Maximum Inhibition (%) crease in specific airway conductance or forced expiratory
volume induced by THC (62). A more likely explanation is
TRC 8.0 60 that the cannabinoids have more than one target.
CBN 5.6 76
CBD 2.8 77
CBG 5.2 100 Another suggestion has been the possibility
OL 9.4 86 that these compounds inhibit platelet-activating factor
(PAF). Recently the abilities of a number of cannabinoids to
inhibit human and rabbit platelet aggregation induced by a
1.6x103M ABC series of agonists including PAF were determined (63). PAF
8.OxlO4M ABA is a natural hormone and is a known mediator of the as-
4 O)(1O4M ABC
2.O,104M COG thmatic/allergenic response in the lungs. It will also induce
2.9x1070 PAP aggregation of blood platelets. CBD was found to antagonise
PAF-induced aggregation of rabbit platelets with an effec-
tive dose of 2.8 x 104M and was measurably more potent
than THC but was less potent than the standard PAF recep-
tor antagonists BN52021 and L652731 (Table 2, Fig. 7).
Both the cannabinoids were shown to inhibit PAF-induced
5HT release in this system but the effects were not dose-re-
lated in platelet-rich plasma. Although it is unlikely that the
cannabinoids are PAF receptor antagonists it is clear that in
this system, as was the case for the PBQ writhing experi-

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ments, the non-centrally active C-S hydroxy compounds
Fig. 7 The effect of a typical antagonist (CBG) on the response of rabbit such as CBD exhibited greater potency than THC.
platelets to PAF (2.9 x 107M)-induced aggregation. CBG was introduced at
arrow 2 in the doses indicated and incubated for 5 mm before the
introduction of PAF at arrow 1. Aggregation was monitored for not less than a
Inflammation
further 5 mm.
The assessment of the anti-inflammatory
effects of the constituents of cannabis using models other
than those involving pain inhibition and hypothermic ef-
fects have often produced contradictory results. For exam-
also examined the analgesic actions of CBD as compared to ple, attempts to inhibit carrageenan-induced edema in the
THC in abdominal constriction tests and found that a dose rat paw following interperitoneal administration of THC
of 200 mg/kg CBD was not active. The analgesic activity of failed (64). Experiments involving oral administration of
OL, CBD, CBN, and THC were compared to the effects pro- THC suggested that THC was 20 times more potent than as-
duced by aspirin in the PBQ model for peripheral pain (57). pirin and twice as potent as hydrocortisone (54). A number
In these experiments it was found that THC was only effec- of related cannabinoids have been assessed for their anti-
tive as an analgesic in doses which were centrally active erythemic effects topically (57). The tetradecanoylphorbol
thereby confirming previous proposals as in (49). However, acetate (TPA) model of mouse skin erythema was used in
it was observed that certain of the other cannabinoids in- these experiments. The minimum dose of TPA (1 pg) which
cluding OL, CBG, and CBD were considerably more potent induced 99 % erythema was applied in acetone to the skin
than THC in this test when their EC5's were compared. In of the animals and 15 mill later the antagonist was applied
fact, CBD with an EC50 of 0.042 mg/kg was about 360 times in ethanol to the same area. The results were read at 4 hand
more potent than aspirin and 590 times more potent than expressed as a percentage inhibition of the TPA alone
THC (Table 1). However, neither CBD nor CBG were 100% treated group. CBD was the most effective anti-erythemic
effective in a manner similar to THC and it would seem that agent tested, producing a 100% inhibition with an effective
at the higher dose levels THC was able to exert an effect cen- dose 50% of 277.1 pg (Table 3).
trally on pain receptors in the brain to augment its
peripheral effects. CBD and CBG although more potent are
less maximally effective than THC as shown in Fig. 6 and Table 3 Inhibition of TPA (1 pg) induced erythema of mouse skin. Results
possibly exert their effects via peripheral receptors only. taken 4 h following the application of the antagonists. N/A = less than 40% in-
These structures are therefore of interest in the develop- hibition at a dose of 1 mg.
ment of mild analgesics devoid of CNS activity. Compound lC50(pg)

Asthma THC 215

CBN N/A
CBD 277
In the past century cannabis has been used CBG 734
for the treatment of bronchial asthma (58) and THC has OL N/A
been shown to induce bronchodilation in asthmatic pa-
tients. The bronchodilatory effect of THC was shown to be
independent of either /-adrenergic (59) or muscarinic in-
hibition (60, 61). Because of the high levels of PG's in the
Separation of Centraifrom PeripheralEffects on a Structural Basis Planta Med. 57(1991), Supplement Issue 11991 S65

The arachidonate cascade as a munoassay (69) as illustrated in Fig. 8. This effect was also
target for cannabinoid activity shown by measurement of thromboxane B2 (TXB2) release
from human polymorphonuclear cells when THC and CBD
The inhibition of arachidonate release and were compared for their abilities to prevent A23 187 stimu-
PG synthesis re-occurs constantly in the literature con- lation of TXB2 (Fig. 9).
cerned with the effects of THC in many different disease
conditions; for example, in glaucoma (21), sedation (26), A number of cannabinoids have been
and as an anti-emetic drug (65, 66). The central hal- examined for their effects upon a microsomal preparation
lucinogenic actions of THC have been correlated with its of cyclooxygenase (70). The cannabinoids were found to in-
ability to stimulate arachidonate mobilisation in cell culture hibit enzyme activity in the 30—40MM concentration range
(67). (Table 4). The effects of the same compounds on soybean
lipoxygenase were also determined and they were found to
The site of action of THC appears not to be inhibit the activity of that enzyme with ID50 of between 2.0—
phospholipase A2 itself. It has been shown with a range of 9.0 riM. There was evidence of competitive inhibition at low
natural cannabinoids used in studies with the enzyme in inhibitor/high substrate concentrations and non-competi-
cell-free systems that there was no difference in the abilities tive inhibition at high inhibitor/low substrate concentra-
of centrally active or non-active compounds to influence en- tions. The effective lipoxygenase inhibitory actions were
zyme activity (68). In fact THC, CBG, CBN, and CBD initially demonstrated in human polymorphonuclear cells stimu-
stimulated enzyme activity in low doses but at higher doses lated with A23187 and the cannabinoids prevented leuko-
enzyme inhibition was recorded (Fig. 4). Opposing effects triene B4 release with 1D50's of between 5 and 8 1iM (Fig. 10).
on arachidonate secretion would be expected depending These effects are characteristic of compounds which inter-
upon the dose of the cannabinoid at the site of action. This fere with peroxide activation of both cyclooxygenase and
effect has been demonstrated in human rheumatoid syno- lipoxygenase. The peripheral effects are therefore complex
vial cells in culture when stimulated with THC, CBN, and involving a dose related stimulation/inhibition of phos-

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CBD and PG release measured by means of a radio-im- pholipase A2 and both cyclooxygenase and lipoxygenase in-
hibition related to their anti-oxidant properties.

150

Table 4 Inhibition of cyclooxygenase microsomal preparation and soy bean

lipoxygenase by cannabinoids.

Compound Inhibition of cyclo- Inhibition of soy bean

100
oxygenase IC50 (iM) lipoxygenase IC50 (izM)
CD
THC 31.8 3.2
CBN 37.7 9.2
50 CBO 39.8 2.9
0.
CBG -ye 2.2
OL 152.8 -ye

0.2 0.66 2.0 6.6 20 66 200 660

CoCCcentratiorC (pg/rol)

Fig. 8 Stimulation of PGE2 release by THC (E), CBN (•), and CBD (0) on
synovial cells.
DO

Ci,
80
-H
CD

200. 0)
'C
0 4.4
60
C
THC 5.,
C CD
0
0 DO
40
.30

0.4
150- 0
C 20
0
C4 -H
0 4-)
-H
C
0
.0
-H
10
100 .0
C
'\.. CflD
I
Cd
0
4-)
C 1 10
0)
0
C
0 Concentration of cannabinoid (,uM) Concentration of cannabinoid
1) ç,1M)

Fig. 9 Stimulation of TXB2 synthesis by CBD ) and THC (•)Fig.

in10purified
Inhibition of LTB4 synthesis by CBD (•) and THC (•) in purified
human polymorphonuclear cell in vitro, human polymorphonuclear cells in vitro.
S66 Planta Med. 57 (1991). Supplement Issue! 1991 FredJ. Evans

100 (2) The presence of a C-S hydroxy group in

A
the structure appears to confer potent peripheral effects.
Basing the natural products upon the numbering system of
0 Inhibition of olivetol (Fig. 5) the compounds can be classified into three
LTB4 production groups:
(a) OL, which is devoid of a terpenoid side
chain at C-6 of the benzene ring, acts as a cyclooxygenase
inhibitor. It is an analgesic of the aspirin class.
Activation of
(b) CBG, exhibits a non-cyclised side chain
LT134 production at C-6. This compound is a lipoxygenase inhibitor with no
anti-cyclooxygenase activity similar to BWA4C.
13
(c) CBD, has a cyclised terpenoid side chain
at C-6. Biochemically, this potent analgesic acts as a dual
0 Inhibition of
cyclooxygenase/lipoxygenase inhibitor. However following
Tx!)2 production
oral administration it appears mainly to exhibit anti-
lipoxygenase effects.

Acknowledgements
lam grateful to Dr. Tudor Evans, Dr. Maryln Bar-
rett, and Dr. Eve Formukong for many of the experimental details,

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0 Activation of to Dr. Laury Garland of the Wellcome Research Laboratories for
Tx!)2 production providing standard drugs, and to the MRC for financial support. I
10 nq/kg am also grateful to the late Prof. James Fairbairn and Dr. Joan Pic-
Cxl
kens whose project this initially was.
11 (A) Inhibition of ionophore-induced LTB4 release by BWA4C,
Fig.
BW755C, and CBD in mouse plasma. Drugs were administered orally after 1 h References
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