Synthesis and analgesic activity of non-classical bicyclic cannabinoid analogues

Article abstract of DOI:10.1211/146080899128735234

The synthesis of a series of non-classical bicyclic cannaboids is described. 3-Phenylcyclohexanols were prepared in three steps from lithium diaryl cuprates. In preliminary tests (acetic acid-induced abdominal constriction and tail-flick tests), the compo

Full text of DOI:10.1211/146080899128735234

Pharm. Pharmacol. Commun. 1999, 5: 495±500
Received May 18, 1999
Accepted June 14, 1999
# 1999 Pharm. Pharmacol. Commun.
Synthesis and Analgesic Activity of Non-classical Bicyclic
Cannabinoid Analogues
SEUNG HWA BAEK, KIL UNG KANG, DU SEOK HAN* AND HYUNG MIN KIM{
Division of Chemistry, Technology and Biological Science, College of Natural Sciences, *Department of
Oral Anatomy, School of Dentistry, and {Department of Oriental Pharmacy, College of Pharmacy,
Wonkwang University, Iksan 570-749, Korea
Abstract
The synthesis of a series of non-classical bicyclic cannaboids is described.
3-Phenylcyclohexanols were prepared in three steps from lithium diaryl cuprates. In
preliminary tests (acetic acid-induced abdominal constriction and tail-¯ick tests), the
compounds were found to have effective analgesic activity, comparable with D1-tetra-
hydrocannabinol. In the ring test for psychotrophic activity, the compounds exhibited no
cannabis-type activity suggesting the separation of analgesic and psychotrophic activity.
These compounds represent a new class of potentially potent non-opiate analgesics.
( )-9-Nor-9-hydroxyhexahydrocannabinnol (HHC,
1) was the ®rst cannabinoid shown to possess
Materials and Methods
analgesic potency approaching that of morphine.
HCC had analgesic potency similar to morphine in
the hot-plate test in mice (Wilson & May 1975;
Chemistry
IR spectra were recorded as thin ®lms (for oils) and
in Nujol mulls on a Perkin-Elmer 457 grating
Wilson et al 1979) and was slightly less potent than
infrared spectrophotometer. UV spectra were
morphine in the Nilsen test (Wilson & May 1976).
Melvin et al (1984) reported that the general
recorded on a Varian techtron 635 UV-vis spectro-
1
photometer. H NMR spectra were obtained on a
dimethyl group on the pyran ring of HHC is not
Bruker WH-60 and WH-300 pulsed FT spectro-
necessary for analgesic activity. 3-[4-(1,1-(Di-
methyheptyl)-2-hydroxyphenyl]cyclohexanol (2)
meter. Chemical shifts are given in ppm relative to
tetramethylsilane as internal standard. Mass spectra
and morphine had equal analgesic potency (Figure
were recorded on a LKB 2091 gas chromatography-
1) (Melvin et al 1984; Mechoulam & Feigenhaum
mass spectrometer at 70 eV. Melting points were
1987; Compton et al 1992).
measured in closed capillaries in a Thomas-Hoover
We previously reported a facile synthesis of 3-[2-
instrument and are uncorrected. Analytical TLC was
(methoxy)-4-alkyl-6-alkoxyphenyl]cyclohexanone
derivatives (7) in moderate yields by reaction of 2-
performed using commercially available silica gel
plates (polygram Sil N-HR=UV254). The plates were
cyclohexen-1-one and 5-alkylphenyl ether (Baek
1993). It seemed of interest to prepare cannabinoid-
visualized with fast blue phenol reagent or by
charring with a solution of CH3OH and H2SO4
like compounds in which the isopropylidene group
(1 : 1). Column chromatography was performed by
is absent and the methyl group is substituted by a
¯ash chromatography or medium pressure liquid
hydroxy group. We report a simple procedure for
chromatography with an FMI pump on Merck Kie-
Michael (1,4) addition of lithium diaryl cuprates to
2-cyclohexen-1-one. The synthesis of these 3-(6-
selgel 60, 230±400 mesh ASTM, with mixtures of
ethyl acetate and light petroleum (bp 60±80ꢀC).
alkoxy-4-alkyl-2-hydroxyphenyl)cyclohexanols(10)
was based on the known analgesic activity in the
non-classical bicyclic cannabinoids (Melvin et al
1984; Mechoulam & Feigenhaum 1987; Compton
et al 1992).
General procedure for the preperation of compounds
7a±d
1-Methoxy- 3- (1,1- dimethylheptyl)- 5- ethoxyben-
zene (1500 mg, 5Á4 mmol) was dissolved in dry ether
Correspondence: S. H. Baek, Division of Chemistry, Tech-
nology and Biological Science, College of Natural Sciences,
Wonkwang University, Iksan 570-749, Korea.
(25 mL) and the solution was cooled to 0ꢀC. The
reaction was placed under a nitrogen atmosphere

496
SEUNG HWA BAEK ET AL
(CDCl3), 0Á91 (3H, t, CH3), 2Á44 (2H, t, benzylic
H), 3Á78 (6H, s, OCH3), 6Á37 (2H, s, arom. H); MS
(rel. intensity), m=z 304 (M ‡ , 71), 261 (27), 247
1
(100); IR (nujol), 1689, 1599, 1569, 1445 cm .
Calculated for C19H28O3: C, 75Á00; H, 9Á21. Found:
C. 75Á10; H, 9Á34.
3 - [2,6 - Dimethoxy - 4 - (1,1-dimethylheptyl)phenyl]
cyclohexanone (7c). Yield 4620 mg (35%), mp
64±65ꢀC; UVmax (EtOH), 272 (e 1300), 278 nm
(1280); NMR d (CDCl3), 0Á94 (3H, t, CH3), 1Á28
(6H, s, CH3), 3Á79 (6H, s, OCH3), 6Á49 (2H, s,
arom. H); MS (rel. intensity), m=z 360 (M ‡ , 50),
276 (87), 275 (100); IR (nujol), 1706, 1600, 1520,
Figure 1. Structures of ( )-9-nor-9-hydroxyhexahydrocanna-
binnol (1), 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclo-
hexanol (2) and 3-(6-alkoxy-4-alkyl-2-hydroxyphenyl)-
cyclohexanols (10).
1
1445 cm . Calculated for C23H36O3: C, 76Á67; H,
10Á00. Found: C, 76Á74; H, 9Á78.
and 3Á6 mL of a n-butyl lithium solution in hexane
(5Á94 mmol) was injected. The reaction mixture
was warmed to room temperature and stirred for
4 h. Cuprous bromide (360 mg, 2Á5 mmol) was
added in one portion. The reaction mixture turned
dark and became homogeneous. After stirring for
5 min, 2-cyclohexen-1-one (240 mg, 2Á5 mmol) was
injected into the solution, and the reaction mixture
was stirred for 15 min at 0ꢀC. Ether (50 mL) and a
saturated ammonium chloride solution (150 mL)
were added. The organic layer was washed with
brine and evaporated to dryness. The oil obtained
was puri®ed by medium pressure liquid chroma-
tography (230±400 mesh ASTM, silica gel 60 for
column chromatography; elution with light petro-
leum).
General procedure for preperation of comounds
8a±d and 9a±c
Compound 7d (566 mg, 1Á5 mmol) was dissolved in
dry tetrahydrofuran (0Á5 mL). Absolute ethanol
(5 mL) was added to the solution. The reaction
mixture was cooled to
40ꢀC, and NaBH4
(113 mg, 3 mmol) was added. The reaction was
stirred for 15 min at 40ꢀC, allowed to warm to
10ꢀC and then quenched by the addition of water
(100 mL). Ether (50 mL) was added, the organic
layer was separated and evaporated to dryness. The
reaction product was separated by medium pressure
LC (elution with ethyl acetate±light petroleum
2Á5 : 97Á5).
cis-3-[2-Methoxy-4-(1,1-dimethylheptyl)-6-ethoxy-
phenyl]cyclohexanol (8d). Yield 294 mg (54%),
UVmax (EtOH), 272 (e 710), 279 nm (640); NMR d
(CDCl3), 0Á89 (3H, t, CH3), 1Á26 (6H, brs, CH3),
1Á66 (3H, t, CH3), 3Á40 (1H, m, C-3H), 3Á78 (3H,
brs, OCH3), 3Á96 (2H, q, J ˆ 4Á0 Hz, methylene H),
4Á60 (1H, brs, OH), 6Á48 (2H, brs, arom. H); MS
(rel. intensity), m=z 376 (M ‡ , 50), 358 (6), 320
(9), 306 (9), 292 (94), 291 (100), 288 (13), 207 (8),
3 - [2 - Methoxy - 4 - (1,1 -dimethylheptyl) - 6 -ethoxy-
phenyl]cyclohexanone (7d). Yield 617 mg, (66%),
UVmax (EtOH), 272 (e 1410), 279 sh nm (1350);
NMR d (CDCl3), 0Á88 (3H, t, CH3), 1Á25 (6H, s,
CH3), 1Á59 (3H, t, CH3), 3Á46 (1H, brt, J ˆ 3Á0 Hz,
C-3H), 3Á77 (3H, s, OCH3), 4Á0 (2H, q, J ˆ 5Á0 Hz,
methylene H), 6Á47 (2H, s, arom. H); MS (rel.
intensity), m=z 384 (M ‡ , 2), 294 (16), 209 (100);
1
1
IR (®lm), 1710, 1600, 1576, 1445 cm .
193 (22); IR (®lm), 3360, 1610, 1576, 1455 cm .
3 - (2 - Methoxy - 4 - pentyl-6-ethoxyphenyl)cyclohex-
anone (7b). Yield 1100 mg (54%), UVmax
(EtOH), 272 (e 1320), 279 nm (1270); NMR d
(CDCl3), 0Á89 (3H, t, CH3), 1Á39 (3H, t, CH3), 2Á53
(2H, t, benzylic H), 3Á18 (1H, t, J ˆ 12 Hz, C-3H),
3Á76 (3H, s, OCH3), 4Á01 (2H, q, J ˆ 6Á0 Hz,
methylene H), 6Á34 (2H, s, arom. H); MS (rel.
intensity), m=z 318 (M ‡ , 93), 287 (21), 261 (100);
cis-,trans-3-[2,6-Dimethoxy-4-(1,1-dimethylheptyl)
phenyl]cyclohexanol (8c, 9c). 9c: Yield 226mg
(5%), mp 77±78ꢀC; UVmax (EtOH), 271 (e 1240),
277 shnm (1150); NMR d (CDCl3), 0Á87 (3H, t, CH3),
1Á30 (6H, s, CH3), 3Á82 (6H, s, OCH3), 4Á19 (1H, br,
OH), 6Á52 (2H, s, arom. H); MS (rel. intensity), m=z
362(M ‡ ,47),344(37),290(25),277(100),259(42);
1
IR (nujol), 3580, 1572, 1443cm . Calculated for
1
IR (®lm), 1700, 1595, 1425 cm .
C23H38O3: C, 76Á24; H, 10Á50. Found: C, 75Á96, H,
10Á53.8c:Yield2850 mg(67%),mp74±75ꢀC;UVmax
(EtOH), 272 (e 960), 278 nm (850); NMR d (CDCl3),
0Á83 (3H, t, CH3), 1Á27 (6H, s, CH3), 3Á78 (6H, s,
OCH3), 6Á48(2H, s, arom. H); MS (rel. intensity), m=z
3 - [2,6 - Dimethoxy - 4 -pentylphenyl]cyclohexanone
(7a). Yield 1600 mg (38%), mp 66±68ꢀC; UVmax
(EtOH), 272 (e 1690), 279 sh nm (1610); NMR d

ANALGESIC CANNABINOID ANALOGUES
497
362(M ‡ ,52),344(11),306(9),277(100);IR(nujol),
The organic extract was washed with water and
evaporated to dryness. The resulting oil was chro-
matographed by medium pressure LC (elution with
ethyl acetate±light petroleum; 2Á5 : 97Á5).
1
3290, 1570, 1442 cm . Calculated for C23H38O3: C,
76Á24; H, 10Á50. Found: C, 76Á23; H, 10Á45.
cis-,trans-3-(2-Methoxy-4-pentyl-6-ethoxylphenyl)
cyclohexanol (8b, 9b). 9b: Yield 66 mg (5Á9%),
UVmax (EtOH), 271 (e 1070), 271 sh nm (900);
NMR d (CDCl3), 0Á85 (3H, t, CH3), 1Á35 (3H, q,
J ˆ 7Á0 Hz, CH3), 2Á56 (2H, t, benzylic H), 3Á71
(3H, s, OCH3), 3Á95 (2H, q, J ˆ 7Á0 Hz methylene
H), 6Á29 (2H, s, arom. H); MS (rel. intensity), m=z
320 (M ‡ , 77), 302 (54), 273 (25), 235 (100), 223
cis-3-[6-Ethoxy-4-(1,1-dimethylheptyl)-2-hydroxy-
phenyl]cyclohexanol (10d). Yield 890mg (47%),
mp 96ꢀC, UVmax (EtOH), 271 (e 1170), 281 nm
(1110); NMRd (CDCl3), 0Á8:3(3H, t, CH3), 1Á20(6H,
s, CH3), 1Á38 (3H, t, J ˆ 6Á8 Hz, CH3), 3Á87 (2H, q,
J ˆ 7Á0 Hz, methylene H), 4Á85 (1H, s, OH), 6Á28 (1H,
d, J ˆ 2Á0 Hz, arom. H), 6Á39 (1H, d, J ˆ 2Á0 Hz, arom.
H); MS (rel. intensity), m=z 362 (M ‡ , 28), 344 (15),
302 (14), 277 (32), 260 (100); IR (®lm), 3450, 1618,
1
(27); IR (®lm), 3400, 1650, 1575, 1420 cm . 8b:
Yield 841 mg (76%), UVmax (EtOH), 271 (e 1000),
278 sh nm (890); NMR d (CDCl3), 0Á87 (3H, t,
CH3), 1Á26 (3H, t, J ˆ 6Á0 Hz, CH3), 2Á53 (2H, t,
benzylic H), 3Á74 (3H, s, OCH3), 3Á97 (2H, q,
J ˆ 7Á0 Hz, methylene H), 6Á33 (2H, s, arom. H);
MS (rel. intensity), m=z, 320 (M ‡ , 93), 302 (24),
277 (19), 264 (22), 235 (100); IR (®lm), 3350,
1
1590, 1450 cm . Calculatedfor C23H38O3: C, 76Á20;
H, 10Á60. Found: C, 76Á30; H, 10Á34.
Acetylation of cis-3-[6-ethoxy-4-(1,1-dimethyl-
heptyl)-2-hydroxyphenyl]cyclohexanol with acetic
anhydride in pyridine led to cis-3-[6-ethoxy-4(1,1-
dimethylheptyl)phenyl]cyclohexanol diacetate 10d
quantitatively, as an oil. UVmax (EtOH), 272 (e
3630), 276 nm (3780); NMR d (CDCl3), 0Á83 (3H,
t, CH3), 1Á22 (6H, s, CH3), 1Á44 (3H, t, J ˆ 7Á0 Hz,
CH3), 2Á00 (3H, s, COCH3), 2Á30 (3H, s, COCH3),
4Á03 (2H, J ˆ 7Á0 Hz, methylene H), 6Á70 (1H, d,
J ˆ 2Á0 Hz, arom. H), 6Á89 (1H, d, J ˆ 2Á0 Hz, arom.
H); MS (rel. intensity), m=z 446 (M ‡ , 44), 404
(31), 386 (6), 361 (44), 344 (78), 260 (100); IR
1
1605, 1579, 1448 cm .
cis -, trans-3-(2,6-Dimethoxy-4-pentylphenyl)cyclo-
hexanol (8a, 9a). 9a: Yield 42 mg (7%), UVmax
(EtOH), 273 (e 920), 280 sh nm (920); NMR d
(CDCl3), 0Á94 (3H, t, CH3), 2Á56 (2H, t, benzylic
H), 3Á67 (1H, m, C-3H), 3Á76 (6H, s, OCH3), 4Á18
(1H, brs, C-1H), 6Á35 (2H, s, arom. H); MS (rel.
intensity), m=z 306 (M ‡ , 100), 287 (89), 2±13
(14), 260 (30), 250 (19), 222 (22); IR (nujol), 3410,
1
(®lm) 1770, 1620, 1575, 1420 cm .
1
1594, 1568, 1436 cm . Calculated for C19H30O3:
cis-3-(6-Methoxy-4-pentyl-2-hydroxyphenyl)cyclo-
hexanol (10a). Yield 135 mg (68%), mp 142±
144ꢀC; UVmax (EtOH) 272 (e 1200), 280 nm
(1110); NMR d (CDCl3) 0Á88 (3H, t, CH3), 2Á47
(2H, t, benzylic H), 3Á16 (1H, m, C-3H), 3Á70 (1H,
m, C-1H), 3Á76 (3H, s, OCH3), 5Á08 (1H, brs, OH),
6Á18 (1H, s, arom. H), 6Á28 (1H, s, arom. H); MS
(rel. intensity), m=z 292 (M ‡ , 32), 274 (44), 246
(15), 231 (27), 218 (100); IR (nujol), 3480, 1598,
C, 74Á51; H, 9Á80. Found: C, 74Á67; H, 9Á96. 8a:
Yield 450 mg (74%), mp 71±72ꢀC; UVmax (EtOH),
271 (e 1220), 279 sh nm (1090); NMR d (CDCl3),
0Á93 (3H, t, CH3), 2Á54 (2H, t, benzylic H), 3Á23
(1H, m, C-3H), 3Á64 (1H, m, C-1H), 3Á77 (6H, s,
OCH3), 6Á36 (2H, s, arom. H); MS (rel. intensity),
m=z 306 (M ‡ , 79), 288 (29), 263 (19), 250 (15),
1
222 (100); IR (nujol), 3360, 1569, 1450 cm .
1
Calculated for C19H30O3: C, 74Á50; H, 9Á80. Found:
1579, 1505, 1445 cm .
C, 74Á72; H, 9Á74.
cis - 3 - (6 - Ethoxy -4-pentyl-2-hydroxyphenyl)cyclo-
hexanol (10b). Yield 128 mg (38%), UVmax
(EtOH), 273 (e 1190), 280 nm (1120); NMR d
(CDCl3), 0Á89 (3H, t, CH3), 1Á39 (3H, t, J ˆ 6Á0 Hz,
CH3), 2Á45 (2H, t, benzylic H), 3Á97 (2H, q,
J ˆ 6Á0 Hz, methylene H), 6Á16 (1H, s, arom. H); 6Á21
(1H, s, arom. H); MS (rel. intensity), m=z 306 (M ‡ ,
39), 280 (47), 260 (15), 259 (15), 245 (27), 232 (100);
General procedure for preperation of compounds
10a±d
Dimethylforamide (10 mL) was added under
nitrogen atmosphere to 50% sodium hydride
(2990 mg, 62Á3 mmol), previously washed with
light petroleum. The reaction vessel was cooled to
0ꢀC and propylmercaptane (5Á28 mL, 57Á1 mmol)
was added slowly using a syringe. After the reac-
tion had subsided (approx. 5 min) the reaction
mixture was brought to room temperature and
compound 8d (1950 mg, 6Á4 mmol) in dimethyl-
foramide (5 mL) was added. The reaction was
heated under re¯ux for 2 h, cooled, poured over 1 M
HCl (300 mL) and extracted with ether (150 mL).
1
IR (nujol), 3320, 1604, 1576, 1500, 1420 cm .
cis-3-[6-Methoxy-4-(1,1-dimethylheptyl)-2-hydroxy-
phenyl]cyclohexanol (10c). Yield 2160 mg (83%),
mp142±144ꢀC;UVmax (EtOH), 272 (e 1310), 279 nm
(1250);NMRd(CDCl3),0Á85(3H,t,CH3),1Á23(6H,s,
CH3), 3Á78(3H,s,OCH3), 4Á91(1H,br, OH),6Á30 (1H,
d, J ˆ 2Á0 Hz, arom. H), 6Á42 (1H, d, J ˆ 2Á0 Hz, arom.

498
SEUNG HWA BAEK ET AL
H); MS (rel. intensity), m=z 348 (M‡ , 29), 330 (19),
were magnetically equivalent and that the two aro-
matic methoxy groups were present. These ®ndings
are consistent with structures 8 and 9 (Wilson &
May 1976) (except for stereochemistry). Equatorial
protons to OH groups have chemical shifts at a
lower ®eld than comparable axial protons (Rao &
Reddy 1992). In 9a the proton on C-1 was at d 4Á18
and in 8a it was at d 3Á64. Thus in 9a the proton was
equatorial and the hydroxyl group was axial, while
in 8a the proton was axial, and the hydroxyl group
was equatorial. As the bulky dimethyl olivetol ring
takes up an equatorial position (in a non-rigid sys-
tem) the hydroxyl groups in 8 and 9 should have the
conformation indicated in Figure 2.
288 (12), 276 (16), 263 (33), 246 (100); IR (nujol),
3540, 1585, 1450cm . Calculated for C22H36O3:
1
75Á86; H, 10Á34. Found: C, 76Á10; H. 10Á24.
Preliminary tests for analgesic activity
The test compounds were dissolved in propylene
glycol and a solution of 2% gum accacia was gra-
dually added to form the suspension. The ®nal
concentration of propylene glycol was never above
5%. Compounds were administered orally as fresh
suspensions (0Á1±0Á2 mL). At least 3 dose levels
were used to determine the dose±response pro®le.
Acetic acid-induced abdominal constriction. Six
mice were tested at each dose level. Thirty minutes
after administration of the drugs, 0Á6% acetic acid
(0Á25 mL) was injected intraperitoneally and the
number of abdominal contractions were counted
over 25 min.
Sodiumpropylmercaptide in hot dimethylfor-
amide under nitrogen effected the monode-
methylation of 3-(6-alkoxy-4-alkyl-2-hydroxy-
phenyl)cyclohexanols 10 (Figure 2). The factors
determining the nucleophilic activity of an anion
have been widely discussed, and there is general
agreement that the reaction rate is dependent on the
polarizability and basicity of the anion (Rao &
Redddy 1992). The propylmercaptide ion with the
very polarizable sulphur atom is thus expected to
be strongly nucleophilic. Compounds 10 were iso-
lated in a virtually pure state and free from surphur
contaminants. Both the excess reagent and the by-
product, methylpropylsulphide, were easily re-
moved by evaporation of the solvents (Davis et al
1979). The reagent was prepared by adding fresh n-
propyl mercaptane to a suspension of ®nely ground
sodium hydride in dry, oxygen-free dimethylfor-
amide under a nitrogen atmosphere, stirring at 0ꢀC
for 5 min. Contact with oxygen results in rapid
oxidation of the mercaptide (Wildes & Martin
1971) and is to be avoided. Dimethylforamide is an
ef®cient solvent for the propylmercaptide ion
because it is stable in strong bases at re¯ux tem-
peratures, and is water-soluble which allows easy
recovery of phenolic products. NMR spectra of
10a±d showed that the two aromatic protons were
not equivalent and that the aromatic, monomethoxy
and monoethoxy groups were presented.
Tail-¯ick test. Three mice were tested at each
dose level. Mice were held in standard receptacles.
The tail was immersed in water at 58ꢀC and
immediately withdrawn on ¯icking. After 5 s rest
the procedure was repeated for a total of 10 times.
Results and Discussion
The preparation of lithium diaryl cuprates (6) and
their use in the synthesis of a non-classical bicyclic
cannabinoid series has been previously reported
(Melvin et al 1984).
Puri®ed cuprous bromide (Furniss et al 1978) was
added to a stirred solution of 5 at 0ꢀC. The mixture
gradually turned black, indicating the formation of
cuprate 6 (Hooz & Layton 1970). The copper-
lithium derivatives of 6 were reacted with
2 - cyclohexen-1-one to yield racemic compounds,
3 - [2 - (methoxy) - 4-alkyl-6-(alkoxy)phenyl]cyclo-
hexanones (7; Figure 2) (Chavdarian & Heathcock
1975). Structural assignments were supported by IR
1
spectra (carbonyl stretching in the 1707±1686 cm
region). NMR spectra indicated that the two aro-
matic protons are magnetically equivalent. Com-
pound 7, on reaction with sodium borohydride gave
a mixture of the racemic cis and trans alcohols, cis
Biological activity
Cannabis has been used as an analgesic for thou-
sands of years (Mechoulam 1986). D1-Tetra-
hydrocannabinol (D1-THC) and several of its
synthetic analogues have been shown to have
analgesic activity in animals and in man. Analgesic
drugs based on the cannabinoid skeleton would be
of considerable interest, if the psychotropic and
analgesic effects could be dissociated. Indications
that these two effects are inherently separable have
been reported (Pertwee 1972; Milne et al 1979).
and
trans-3-(2-methoxy-4-alkyl-6-alkoxy-phe-
nyl)cyclohexanols (9 and 8, respectively). The
predominant isomer is that in which the hydroxyl
and aryl groups are cis (i.e. compounds in the trans
series). TLC revealed that the trans series was more
polar than the cis series. IR spectra showed the
presence of the hydroxyl group in the 3584±
1
3290 cm region. NMR spectra of 8a, 8c, 9a and
9c indicated that the two aromatic hydrogen atoms

ANALGESIC CANNABINOID ANALOGUES
499
Figure 2. Synthesis of 3-(6-alkoxy-4-alkyl-2-hydroxyphenyl)cyclohexanols 10a±d. Reagents: i. CuBr, 0ꢀC; ii. absolute C2H5OH,
40ꢀC, NaBH4; iii. DMF, 50% NaH, C3H7SH.
In preliminary tests, the analgesic activity of
compounds 10a±d was found to be comparable, or
greater than, that of THC (Table 1). In the ring test,
the compounds exhibited no cannabis-type activity,
indicating separation of analgesic and psychotropic
activity (Table 2). This is of considerable impor-
tance as it opens a new route for the synthesis of
potent non-opiate analgesics.
Further investigation of the analgesic activity of
these compounds is merited. Potential addictive-
ness must be considered and more extensive tests
for possible psychotropic activity are required.

500
SEUNG HWA BAEK ET AL
Compton, E. R., Johnson, M. R., Melvin, L. S., Martin, B. R.
Table 1. Preliminary analgesic tests.
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cannabinoid analogs: classi®cation as cannabimimetic
agents. J. Pharmacol. Exp. Ther. 260: 201±209
Davis, S. G., Green, M. L. H., Mingos, D. M. P. (1979)
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50: 1±33
Furniss, B. S., Hannaford, A. T., Rogers, V., Smith, P. W. G.,
Tatchell, A. R. (1978) Vogel's Textbook of Practical
Organic Chemistry, 4th edn, Longman Inc., New York
Hooz, J., Layton, R. B. (1970) Reaction of conjugated enones
with divinyl copperlithium tri-n-butylphosphine complex. A
new preparation of g,d-unsaturated ketones. Can. J. Chem.
48: 1626±1628
1
ED50 (mg kg )
Compound
Acetic acid-induced
abdominal constriction test
Tail-¯ick test
Morphine
D1-THC
10a
10c
10d
4 (p.o.), 2 (s.c.)
5 (p.o.)
10 (p.o.)
20 (p.o.), 20 (s.c.)
50 (p.o.)
±
4 (p.o.), 2 (s.c.)
0Á2 (s.c.)
20 (p.o.)
5 (p.o.)
Jackman, L. M. (1959) NMR Spectroscopy in Organic Chem-
istry. Pergamon Press, New York, p. 239
Mechoulam, R. (1986) The pharmacohistory of Cannabis
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Table 2. Measurement of cannabis-like activity using the
ring test.
Compound
Dose (mg kg 1, p.o.)
Ring index
D1-THC
10a
10b
10c
10d
1
5
5
5
5
40Á0
5Á6
8Á1
7Á6
8Á2
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Acknowledgements
This work was supported by Wonkwang University,
Korea, and by partial grants from the Korea Sci-
ence and Engineering Foundation (98-16-01-04-A-
3). We are grateful to Professor R. Mechoulam and
the Department of Natural Products, the Hebrew
University of Jerusalem.
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hydroxycannabinoid-like compounds. Synthesis and evalua-
tion of analgesic and behavioral properties. J. Med. Chem.
22: 886±888
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