1-Methoxy-, 1-deoxy-11-hydroxy- and 11-hydroxy-1-methoxy-Δ8-tetrahydrocannabinols: New selective ligands for the CB2 receptor

Article abstract of DOI:10.1016/S0968-0896(02)00331-0

Three series of new cannabinoids were prepared and their affinities for the CB₁ and CB₂ cannabinoid recptors were determined. These are the 1-methoxy-3-(1′,1′-dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(1′,1′-dimethylalkyl)- and 11-hydroxy-1-methoxy-3-(1′,1′-dimethylalkyl)-Δ ⁸-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB₂ receptor than for the CB₁ receptor, however only 1-methoxy-3-(1′,1′-dimethylhexyl)-Δ⁸-THC (JWH-229, 6e) has effectively no affinity for the CB₁ receptor (K_i=3134±110 nM) and high affinity for CB₂ (K_i=18±2 nM).

Full text of DOI:10.1016/S0968-0896(02)00331-0

Bioorganic & Medicinal Chemistry 10 (2002) 4119–4129
1-Methoxy-, 1-Deoxy-11-hydroxy- and
11-Hydroxy-1-methoxy-D8-tetrahydrocannabinols:
New Selective Ligands for the CB2 Receptor
John W. Huffman,a,* Simon M. Bushell,a John R. A. Miller,a Jenny L. Wileyb
and Billy R. Martinb
aHoward L. Hunter Laboratory, Clemson University, Clemson, SC 29634-1905, USA
bDepartment of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University,
Richmond, VA 23298-0613, USA
Received 8 March 2002; accepted 11 June 2002
Abstract—Three series of new cannabinoids were prepared and their affinities for the CB1 and CB2 cannabinoid recptors were
determined. These are the 1-methoxy-3-(10,10-dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(10,10-dimethylalkyl)- and 11-hydroxy-1-meth-
oxy-3-(10,10-dimethylalkyl)-Á8-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended
to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB2 receptor than for the CB1 receptor, however
only 1-methoxy-3-(10,10-dimethylhexyl)-Á8-THC (JWH-229, 6e) has effectively no affinity for the CB1 receptor (Ki=3134ꢀ110 nM)
and high affinity for CB2 (Ki=18ꢀ2nM).
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
Although it has been known for some time that canna-
binoids are involved in immunomodulation,11 the dis-
covery that the CB2 receptor is expressed primarily in
cells of the immune system led to the suggestion that the
CB2 receptor was responsible for the immunomodula-
troy effects of cannabinoids.5 This suggestion has been
confirmed recently by the observation that these immu-
nomodulatory effects are absent in CB2 receptor
knockout mice.12 Although there is evidence that the
CB2 receptor is not expressed in the central nervous
system,13 it has recently been found that this receptor is
expressed in adult rat retina.14
The complex pharmacological effects of cannabinoids
are considered to be mediated through at least two G-
protein-coupled, transmembrane receptors. One of
these, designated as CB1, is found predominantly in the
central nervous system and is responsible for most of
the overt pharmacological effects of cannabinoids.1ꢁ4
A
second receptor, designated CB2, was originally identified
from macrophages present in the spleen, and is expressed
primarily in the periphery.5 Very recently evidence has
been presented for the existence of a third cannabinoid
receptor, which has been detected in mouse brain.6
Although it has been known for several years that the
CB2 receptor is expressed in cells in the immune system,
it has only been within the past few years that specific
effects mediated by this receptor have been recognized.
These effects included the discovery that a CB2 selective
receptor ligand, JWH-133, is effective in reducing spasti-
city in the mouse model of multiple sclerosis,15 and the
same CB2 selective ligand also inhibits the in vivo growth
of glioma tumors.16 Other effects modulated by the CB2
receptor include peripheral antinociception,17 and at least
in part, the antitumor properties of ajulemic acid.18
It is generally accepted that the CB1 receptor is impli-
cated in eliciting the in vivo effects of cannabinoids; a
good correlation has been found between the CB1
receptor affinities of a series of cannabinoids and their
in vivo effects.7,8 These in vivo effects are blocked by
SR141716A, an inverse agonist for the CB1 receptor,
and are absent in CB1 receptor knockout mice.9,10
*Corresponding author. Tel.: +1-864-656-3133; fax: +1-864-656-
6613; e-mail: huffman@clemson.edu
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00331-0

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J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
Several years ago we reported that 3-(10,10-dimethyl-
heptyl)-1-deoxy-11-hydroxy-Á8-tetrahydrocannabinol (1-
deoxy-11-hydroxy-Á8-THC-DMH, deoxy-HU-210, JWH-
051, 1), a traditional cannabinoid lacking a 1-hydroxyl
group, has very high affinity for the CB1 receptor
(Ki=1.2ꢀ0.1 nM), and exhibits characteristic cannabi-
noid in vivo pharmacology. Cannabinoid 1 also has
exceptionally high affinity for the CB2 receptor
(Ki=0.032ꢀ0.019 nM).19 A second 1-deoxycannabinoid,
3-(10,10-dimethylheptyl)-1-deoxy-Á8-THC (1-deoxy-Á8-
THC-DMH, JWH-057, 2), is also potent in vivo, has
significant affinity for the CB1 receptor (Ki=23ꢀ7 nM),
and nearly ten times greater affinity for the CB2 receptor
(Ki=2.9ꢀ1.6 nM).19 Based on these observations, we
synthesized a number of 1-deoxy-Á8-THC analogues.20
Several of these compounds have high affinity for the
CB2 receptor, with low affinity for the CB1 receptor, and
one of them, 3-(10,10-dimethylbutyl)-1-deoxy-Á8-THC
(JWH-133, 3) with Ki=3.4ꢀ1.0 nM at CB2 and
677ꢀ132nM at CB 1 is highly selective. In the same
publication, we developed some preliminary structure–
activity relationships (SAR) for the CB2 receptor. These
preliminary SAR demonstrated that a 10,10-dimethyl
group leads to enhanced affinity for the CB2 receptor,
and that in the 10,10-dimethyl-1-deoxy-Á8-THC series,
compounds with a three to seven carbon side chain all
have high affinity for the CB2 receptor (Ki=<2 0 nM).
Also, affinity for both receptors is enhanced by the pre-
sence of an 11-hydroxyl group.
In view of the continuing recognition of the importance
of the CB2 receptor, we have taken advantage of the
currently available knowledge of the SAR of 1-meth-
oxy- and 1-deoxy-Á8-THC analogues to design three
series of CB2 selective cannabinoid receptor ligands.
Based on the knowledge that the side chain in the 1-
deoxy-Á8-THC series can be shortened significantly
without seriously attenuating CB2 receptor affinity, and
that an 11-hydroxyl enhances both CB1 and CB2 recep-
tor affinities,20 the initial synthetic targets included a
series of 1-deoxy-3-(10,10-dimethylalkyl)-11-hydroxy-Á8-
THC analogues. Since 1-methoxy-Á8-THC-DMH (4) is
also a CB2 selective cannabinoid ligand,20,21,23 a series
of 3-(10,10-dimethylalkyl)-1-methoxy-Á8-THCs was also
prepared. The third series of CB2 selective compounds
consisted of 11-hydroxy-3-(10,10-dimethylalkyl)-1-meth-
oxy-Á8-THC analogues which combined the structural
features of the other two series.
Results
The 1-methoxy-Á8-THC analogues (6a–6e) were prepared
by direct methylation of the corresponding Á8-THC (7a–
7e) using methyl iodide/KOH in DMF in unoptimized
yields of 43–97% (Scheme 1). The cannabinoid substrates
are all known compounds which were prepared by the
acid catalyzed condensation of the corresponding alkyl
resorcinol with trans-p-menthadienol.20,24,25
The 1-deoxy-11-hydroxy-Á8-THCs (9a–9e, Scheme 2)
were prepared from the corresponding 1-deoxy-Á8-
THC (8a–8e, Scheme 1) by initial selenium dioxide oxi-
dation to the 11-oxo compounds (10a–10e), followed by
reduction of the aldehyde. The requisite 1-deoxy-Á8-
THCs (8a–8e) were prepared from the corresponding
Á8-THC by conversion to the phosphate ester, followed
by dissolving metal reduction using procedures we have
described previously (Scheme 1).20 Selenium dioxide
oxidation of cannabinoids 8a–8e using a procedure
developed by Razdan’s group provided aldehydes 10a–
10e,26 which were reduced to the 11-hydroxy analogues
without extensive purification. Lithium aluminum
hydride reduction of aldehydes 10a–10e provided alcohols
9a–9e in modest yields for the two steps. Improved
yields of alcohols 9 were obtained by the method of
Luche (sodium borohydride-cerium (III) chloride).27
In the 11-hydroxy-3-(10,10-dimethylalkyl)-1-methoxy-
Á8-THC series, in addition to the dimethylethyl through
dimethylhexyl analogues (11a–11e), 11-hydroxy-3-(10,10-
dimethylheptyl)-1-methoxy-Á8-THC was prepared. The
dimethylheptyl analogues in the methyl ether series (4)
and 1-deoxy-11-hydroxy (1) series had been prepared
previously.19ꢁ21 The initial synthetic approach to this
series of compounds was based upon a procedure
developed by Mechoulam for the synthesis of 11-
hydroxy-Á8-THC-DMH (HU-210), and which we had
used previously in the synthesis of 11-hydroxy-(10S,20R)-
dimethylheptyl-Á8-THC.28,29 In a modification of this
protocol, the appropriate resorcinol is condensed with
4-hydroxymyrtenyl pivalate (12, Scheme 3) to provide
the 11-pivaloyloxy-Á8-THC (13a and 13b). Conversion
A group at Merck Frosst described two 1-methoxy
cannabinoids, 1-methoxy-Á8-THC-DMH (4), and 1-
methoxy-Á9(11)-THC-DMH (5) which were reported to
have affinities for the CB2 receptor in the 20 nM range,
and virtually no affinity for the CB1 receptor.21 An
additional CB2 selective agonist, HU-308 was reported
by Hanus et al.; this compound has no affinity for the
CB1 receptor (Ki>10,000 nM), and good affinity for the
CB2 receptor (Ki=22.7ꢀ3.9 nM).22 HU-308 is inactive
in the mouse behavioral tetrad, reduces blood pressure
and shows peripheral analgesic activity. These hypo-
tensive and analgesic effects are blocked by SR-144528,
a CB2 antagonist.

J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
4121
Scheme 1. (a) HOTs/C6H6, 80 ꢂC; (b) CH3I/KOH/DMF, 25 ꢂC; (c) NaH/THF, 0 ꢂC then (C2H5O)2P(O)Cl; (d) Li/NH3, THF, ꢁ78 ꢂC.
ꢂ
ꢂ
.
Scheme 2. (a) SeO2/EtOH, 80 C; (b) LiAlH4/THF, 25 C or NaBH4/CeCl3 7H2O/MeOH.
to the methyl ether, followed by reduction with lithium
aluminum hydride provides the corresponding
11-hydroxy-3-(10,10-dimethylalkyl)-1-methoxy-Á8-THC.
This procedure was employed to prepare the first two
members of the homologeous series (11a and 11b),
however the overall yields were quite low. The other
three members of this series (11c–11e) were prepared
from the corresponding 1-methyl ether (6c–6e) by sele-
nium dioxide oxidation followed by reduction of the
corresponding aldehyde in a procedure analogous to that
employed for the synthesis of the 1-deoxy-11-hydroxy
compounds (Scheme 2). Reduction of the 11-oxo com-
pounds using Luche conditions27 gave excellent yields of
the corresponding 11-hydroxy cannabinoids (11c–11e).
the CB1 receptor were determined by measuring their
ability to displace the potent cannabinoid [3H] CP
55,940 from its binding site in a membrane preparation
from rat brain as described by Compton et al.8 Affinities
for the CB2 receptor were determined by measuring the
ability of the compounds to displace [3H] CP 55,940
from a cloned human receptor preparation using the
procedure described by Showalter et al.30 The results of
these determinations are summarized in Table 1. Also
included in Table 1 are the receptor affinities for can-
nabinoids 1–4, Á8- and Á9-THC.
In the 1-methoxy-Á8-THC series (6a–6e) none of these
compounds have appreciable affinity for the CB1 receptor,
with Ki values of 3134ꢀ110 nM for the dimethylhexyl
analogue (6e) to Ki>10,000nM for the dimethylethyl
through dimethylbutyl compounds (6a–6c). This series
The affinities of 1-methoxy-, 11-hydroxy- and 11-
hydroxy-1-methoxy-Á8-THC analogues 6, 9 and 11 for

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J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
ꢂ
ꢂ
ꢂ
.
.
Scheme 3. (a) BF3 Et2O/CH2Cl2, ꢁ20 C; (b) CH3I/KOH/DMF, 25 C; (c) LiAlH4/THF, 25 C or NaBH4/CeCl3 7H2O/MeOH.
Table 1. Receptor affinities (meanꢀSEM) of 1-deoxycannabinoids and related compounds
Compound
Ki (nM)
CB1
CB2
Ratio CB2/CB1
Á9-THC
41ꢀ2a
44ꢀ12c
36ꢀ10b
44ꢀ17c
1.1
1.0
40
Á8-THC
1-Deoxy-11-hydroxy-3-(10,10-dimethylheptyl)-Á8-THC (1)
1-Deoxy-3-(10,10-dimethylheptyl)-Á8-THC (2)
3-(10,10-Dimethylheptyl)-1-methoxy-Á8-THC (4)
3-(10,10-Dimethylheptyl)-1-methoxy-Á8-THC (4)
3-(10,10-Dimethylbutyl)-1-deoxy-Á8-THC (3)
1.2ꢀ0.1d
22.8ꢀ7.3d
713ꢀ68
0.03ꢀ0.02d
2.9ꢀ1.6d
57ꢀ1212
65ꢀ8.42c
3.4ꢀ1.0c
1867ꢀ867
1404ꢀ66
325ꢀ70
43ꢀ3
7.9
92 ꢀ104c
677ꢀ132c
>10,000
>10,000
>10,000
4001ꢀ282
3134ꢀ110
14
199
5.4
7.1
31
3-(10,10-Dimethylethyl)-1-methoxy-Á8-THC (6a)
3-(10,10-Dimethylpropyl)-1-methoxy-Á8-THC (6b)
3-(10,10-Dimethylbutyl)-1-methoxy-Á8-THC (6c)
3-(10,10-Dimethylpentyl)-1-methoxy-Á8-THC (6d)
3-(10,10-Dimethylhexyl)-1-methoxy-Á8-THC (6e)
1-Deoxy-11-hydroxy-3-(10,10-dimethylethyl)-Á8-THC (9a)
1-Deoxy-11-hydroxy-3-(10,10-dimethylpropyl)-Á8-THC (9b)
1-Deoxy-11-hydroxy-3-(10,10-dimethylbutyl)-Á8-THC (9c)
1-Deoxy-11-hydroxy-3-(10,10-dimethylpentyl)-Á8-THC (9d)
1-Deoxy-11-hydroxy-3-(10,10-dimethylhexyl)-Á8-THC (9e)
11-Hydroxy-3-(10,10-dimethylethyl)-1-methoxy-Á8-THC (11a)
11-Hydroxy-3-(10,10-dimethylpropyl)-1-methoxy-Á8-THC (11b)
11-Hydroxy-3-(10,10-dimethylbutyl)-1-methoxy-Á8-THC (11c)
11-Hydroxy-3-(10,10-dimethylpentyl)-1-methoxy-Á8-THC (11d)
11-Hydroxy-3-(10,10-dimethylhexyl)-1-methoxy-Á8-THC (11e)
11-Hydroxy-3-(10,10-dimethylheptyl)-1-methoxy-Á8-THC (11f)
93
18ꢀ2174
70 18ꢀ215
5.6ꢀ1.7
3.4ꢀ0.5
1.6ꢀ0.03
0.52ꢀ0.03
333ꢀ104
85ꢀ2
2
ꢀ58
187ꢀ23
84ꢀ16
33
25
5.5
3.5
5.6
1
12
9.1
11
8.8ꢀ1.4
1.8ꢀ0.3
1856ꢀ148
1008ꢀ117
347ꢀ34
40ꢀ6
28ꢀ1
4.4ꢀ0.3
1.4ꢀ0.1
1.0ꢀ0.3
15ꢀ3
14ꢀ3
14
aref 8.
bref 30.
cref 20.
dref 19.
of compounds does, however, show considerable selec-
tivity for the CB2 receptor. There is an incremental
increase in CB2 receptor affinity with Ki=1867ꢀ867 for
the dimethylbutyl compound (6c), increasing to
Ki=18ꢀ2nM for 3-(1 0,10-dimethylhexyl)-1-methoxy-
Á8-THC (6e). 3-(10,10-Dimethylhexyl)-1-methoxy-Á8-
THC (6e) shows nearly 175 fold selectivity for the CB2
receptor. For 3-(10,10-dimethylheptyl)-1-methoxy-Á8-
THC (4) we reported Ki=924ꢀ104 nM at CB1 and
65ꢀ8 nM at CB2.20 However, for the same compound,
Gareau et al. found Ki=15,850ꢀ2960 nM at CB1 and
20ꢀ12nM at CB2.21 Ross et al. found somewhat different
values, Ki=1043ꢀ296 nM at CB1 and 6.4ꢀ2.2 nM at
CB2.23 In view of these variations in the reported data
for 1-methoxy-Á8-THC-DMH (4), the preparation of
this compound was repeated, and new binding data for

J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
4123
both receptors were obtained. The new data,
Ki=713ꢀ68 nM at CB1 and Ki=57ꢀ12nM at CB 2 are
essentially the same as those we reported previously.20
receptor affinity as the length of the side chain increases
from two to seven carbon atoms. These compounds also
show from modest to high affinity for the CB1 receptor,
increasing from Ki=270ꢀ58 nM for the dimethylethyl
analogue (9a) to Ki=1.2ꢀ0.1 nM for the dimethylheptyl
compound (1) reported previously.19 The relatively high
CB1 receptor affinities for the compounds in this series
may be attributed to the 11-hydroxyl group serving as a
surrogate for the phenolic hydroxyl in more traditional
cannabinoids as suggested by molecular modeling studies
carried out on 1, combined with a 3-(10,10-dimethyl-
alkyl) substituent of sufficient length to interact with the
lipophilic portion of the receptor.19
The differences in receptor affinity between those we
have determined and those determined by other groups
may be due to a number of factors, including somewhat
different cell lines and slightly different laboratory pro-
cedures employed in carrying out the determinations.
As mentioned above, our CB1 receptor affinities were
determined using a rat brain membrane preparation
while Gareau et al. employed a human CB1 receptor
preparation which was not described in detail.21 The
binding assays described by Ross et al. were carried out
using CHO (Chinese hamster ovary) cells transfected
with human CB1 and CB2 receptors.23 Our CB2 data
were obtained as described in the Experimental using
HEK (human embronyic kidney) cells transfected with
human CB2 receptors.
The compounds in the 1-methoxy series (4 and 6a to 6e)
all have little affinity for the CB1 receptor, with CB2
affinities ranging from very slight for the dimethylethyl
analogue (6a, Ki=1867ꢀ867 nM) to quite high for the
dimethylhexyl compound (6e, Ki=18ꢀ2nM). As
reported previously, the dimethylheptyl analogue (4)
has little affinity for the CB1 receptor and moderate
affinity for the CB2 receptor. The dimethylhexyl methyl
ether (6e) is a highly selective CB2 receptor ligand with
good affinity for the CB2 receptor and very little affinity
for the CB1 receptor.
The 1-deoxy-11-hydroxy-Á8-THC analogues (9a–9e)
have from modest to very high affinity for the CB1
receptor, and show moderate selectivity for the CB2
receptor. The first member of the homologeous series, 1-
deoxy-3-(10,10-dimethylethyl)-11-hydroxy-Á8-THC (9a)
has Ki=270ꢀ58 nM at the CB1 receptor, with
Ki=18ꢀ2nM at CB 2. Receptor affinity at CB1
improves to Ki=1.8ꢀ0.3 nM and CB2 affinity increases
to Ki=0.52ꢀ0.03 nM for the dimethylhexyl analogue
(9e). The most selective compound in this series is the
dimethylpropyl analogue (9b) which has 25 fold greater
The compounds of the 11-hydroxy-1-methoxy series
(11a–11f) are intermediate between those of the other
two series of ligands in their affinities for both receptors.
The lower members of this series (11a–11c) have little
affinity for the CB1 receptor with Ki=1856ꢀ148 nM for
the dimethylethyl analogue (11a) and Ki=347ꢀ34 nM
for the dimethylbutyl compound (11c). The higher
members of this series have from moderate affinity (11d,
Ki=40ꢀ6 nM) for the CB2 receptor to high affinity for
the dimethylhexyl (11e) and dimethylheptyl (11f) analo-
gues. The affinities of 11e and 11f are identical within
experimental error for each receptor, with Ki=14 nM at
CB1 and 1.2nM at CB 2.
affinity for the CB2 receptor (Ki=187ꢀ2 3 nM at CB
1
and Ki=5.6ꢀ1.7 nM at CB2).
The compounds in the 11-hydroxy-3-(10,10-dimethy-
lalkyl)-1-methoxy-Á8-THC series (11a–11f) also show
moderate selectivity for the CB2 receptor, but the CB1
receptor affinities increase significantly in the higher
members of this homologous series. For 11-Hydroxy-3-
(10,10-dimethylethyl)-1-methoxy-Á8-THC (11a), Ki=1856ꢀ
148 nM at CB1 and Ki=333ꢀ104 at CB2. Affinity for
both receptors improves to Ki=15ꢀ3 nM at CB1 for
11-hydroxy-3-(10,10-dimethylhexyl)-1-methoxy-Á8-THC
(11e) with Ki=1.4ꢀ0.3 nM at CB2. The receptor affinities
for 11-hydroxy-3-(10,10-dimethylheptyl)-1-methoxy-Á8-
THC (11f) are essentially identical to those for the
dimethylhexyl analogue, with Ki=14ꢀ3 nM at CB1 and
1.0ꢀ0.3 at CB2.
In terms of the SAR for 1-methoxy-, 1-deoxy-11-
hydroxy and 11-hydroxy-1-methoxy-Á8-THC analo-
gues, it is apparent that an 11-hydroxyl substituent
enhances affinity for both the CB1 and CB2 receptors.
Also, in the 3-(1,1-dimethylalkyl) series the length of the
side chain plays a critical role in determining affinity for
both receptors. It is somewhat important for CB2 affi-
nity, particularly in the methyl ether series (6), but for
significant CB1 affinity a chain length of at least five
carbon atoms is essential.
The data summarized in Table 1, are in general agree-
ment with the preliminary SAR for the CB2 receptor
which we developed based upon our study of 1-deoxy-
Á8-THC analogues.20 In the 10,10-dimethyl-1-deoxy-Á8-
THC series described previously, those compounds with
a three to seven carbon side chain (2 and 8b–8e) all have
high affinity for the CB2 receptor (Ki=<20 nM). Of the
three new series of CB2 selective cannabinoid receptor
ligands, only the 1-deoxy-11-hydroxy-Á8-THC analogues
(1 and 9a–9e) show uniformly high affinity for the CB2
receptor, with Ki=0.032ꢀ0.019 nM for the dimethyl-
heptyl analogue (1)19 to Ki=18.1ꢀ1.8 nM for the lowest
member of the homologous series (9a). As would be
expected there is a progressive improvement in CB2
In summary, although several of these compounds show
selectivity for the CB2 receptor, only five of them, 1-
methoxy cannabinoids 6d and 6e, 1-deoxy-11-hydroxy
compounds 9a and 9b, and 11-hydroxy-3-(10,10-dime-
thylbutyl)-1-methoxy-Á8-THC (11c) have a combina-
tion of high affinity for the CB2 receptor and little
affinity for the CB1 receptor. Only 3-(10,10-dimethyl-
hexyl)-1-methoxy-Á8-THC (6e, JWH-229) with Ki=
3134ꢀ110 nM at CB1 and Ki=18ꢀ2nM at CB 2 is
comparable in selectivity to 1-deoxy-3-(10,10-dimethyl-
hexyl)-Á8-THC (3, JWH-133) with Ki=677ꢀ132nM at
CB1 and Ki=3.4ꢀ1.0 nM at CB2.20 Although JWH-229

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J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
(6e) has slightly less affinity for the CB2 receptor than
JWH-133 (3), it has significantly lower affinity for CB1,
and is thus a potentially useful CB2 selective cannabi-
noid ligand with very little affinity for CB1.
ꢁ210ꢂ (c=0.29, CH2Cl2) HRMS calcd for C22H32O2:
328.2404, found 328.2402.
1-Methoxy-3-(10,10-dimethylethyl)-D8-THC(6a). Meth-
oxy cannabinoid 6a was prepared by the procedure
described above for the preparation of 6b. Methylation
of 0.384 g (1.28 mmol) of 7a20 gave 0.173 g (43%) of 6a
as a colorless oil: 1H NMR (300 MHz, CDCl3) d 1.10 (s,
3H), 1.29 (s, 9H), 1.38 (s, 3H), 1.74 (s, 3H), 1.76–1.82
(m, 3H), 2.11–2.14 (m, 1H), 2.65 (td, J=4.5, 10.9 Hz,
1H), 3.15 (dd, J=3.8, 17.3 Hz, 1H), 3.81 (s, 3H), 5.41 (d,
J=4.6 Hz, 1H), 6.44 (d, J=1.6 Hz, 1H), 6.48 (d,
J=1.6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 18.5,
23 (5), 27.6, 28.0, 31.2, 31.7, 34.7, 36.1, 45.0, 55.1, 76.5,
100.2, 107.6, 111.7, 119.2, 135.0, 150.9, 154.0, 158.7; MS
(EI) m/z 314 (52), 299 (8), 246 (13), 231 (100); [a]D20
ꢁ206ꢂ (c=2.65, CH2Cl2); HRMS calcd for C21H30O2:
314.2245, found 314.2246.
Experimental
General
IR spectra were obtained using Nicolet 5DX or Magna
1
spectrometers; H and 13C NMR spectra were recorded
on a Bruker 300AC spectrometer. Mass spectral ana-
lyses were performed on a Hewlett-Packard 5890A
capillary gas chromatograph equipped with a mass sen-
sitive detector. HRMS data were obtained in the Mass
Spectrometry Laboratory, School of Chemical Sciences,
University of Illinois. Ether and THF were distilled
from Na-benzophenone ketyl immediately before use,
and other solvents were purified using standard proce-
dures. Column chromatography was carried out on
Sorbent Technologies silica gel (32–63 mm) using the
indicated solvents as eluents. All new compounds were
homogeneous to TLC and 13C NMR. All target com-
pounds were homogeneous to GLC or TLC in two dif-
ferent solvent systems. TLC was carried out using
200 mm silica gel plates using the indicated solvents.
GLC analyses were performed on the Hewlett-Packard
5890A GC/MS using a 60 m carbowax column and
helium gas as a carrier. An initial column temperature
of 60 ꢂC was employed and the temperature was
increased at a rate of 1.5 ꢂC/min to a maximum
temperature of 300 ꢂC with a total run time of 20 min.
Elemental analyses were performed by Atlantic Micro-
lab, Norcross, GA.
1-Methoxy-3-(10,10-dimethylbutyl)-D8-THC(6c). Meth-
oxy cannabinoid 6c was prepared by the procedure
described above for the preparation of 6b. Methylation
of 0.782g (2.38 mmol) of 7c20 gave 0.461 g (43%) of 6c
as a colorless oil: 1H NMR (500 MHz, CDCl3) d 0.82(t,
J=7.4 Hz, 3H), 1.09 (s, 3H), 1.05–1.15 (m, 2H), 1.25 (s,
6H), 1.38 (s, 3H), 1.49–1.55 (m, 2H), 1.70 (s, 3H), 1.74–
1.85 (m, 3H), 2.09–2.16 (m, 1H), 2.66 (td, J=4.6,
11.0 Hz, 1H), 3.16 (dd, J=3.2, 16.5 Hz, 1H), 3.78 (s,
3H), 5.42(d, 4.1H), 6.38 (d, J=0.9 Hz, 1H), 6.43 (d,
J=0.9 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) d 14.9,
18.1, 18.5, 23.7, 27.7, 28.1, 28.9, 29.0, 31.8, 36.3, 37.8,
45.2, 47.2, 55.2, 76.9, 100.9, 108.3, 111.7, 119.4, 135.1,
149.7, 154.1, 158.8; MS (EI) m/z 342(37), 300 (100), 286
(20), 259 (38); [a]D20 ꢁ258ꢂ (c=0.79, CHCl3); HRMS
calcd for C23H34O2: 342.2564, found 342.2559.
1-Methoxy-3-(10,10-dimethylpropyl)-D8 -THC(6b). To a
solution of 0.569 g (1.8 mmol) of 3-(10,10-dimethylpro-
pyl)-Á8-THC (7b)20 in 14 mL of dry DMF under N2 was
added 0.151 g (2.7 mmol) of KOH and 0.33 mL
(5.4 mmol) of methyl iodide. The reaction mixture was
stirred for 48 h at ambient temperature before being
quenched by the addition of 2mL of aqueous NH 4Cl
and removal of the DMF in vacuo. The residue was
extracted with three portions of ether and the combined
organic extracts were dried (MgSO4) and concentrated
in vacuo. The crude product was initially purified by dry
flash chromatography (petroleum ether:ether, 97:3) fol-
lowed by gradient elution chromatography (petroleum
ether:dichloromethane, 9:1 to 8:1) to afford 0.309 g
(52%) of 6b as a colorless oil. Further chromatography
(petroleum ether:dichloromethane, 85:15) of 0.104 g of
this material gave 0.100 g of pure 6b, Rf 0.46 (petroleum
ether: dichloromethane, 85:15); 1H NMR (500 MHz,
CDCl3) d 0.79 (t, J=7.1 Hz, 3H), 1.09 (s, 3H), 1.24 (s,
6H), 1.38 (s, 3H), 1.54–1.60 (m, 2H), 1.70 (s, 3H), 1.74–
1.81 (m, 3H), 2.12–2.14 (m, 1H), 2.67 (td, J=4.7,
11.1 Hz, 1H), 3.15 (dd, J=4.7, 17.1 Hz, 1H), 3.81 (s,
3H), 5.42(br. s, 1H), 6.38 (d, J=1.6 Hz, 1H), 6.42(d,
J=1.6 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) d 14.1,
18.4, 23.4, 27.8, 27.9, 28.7, 31.7, 36.3, 37.6, 44.3, 45.0,
55.1, 76.4, 100.7, 108.3, 111.2, 119.2, 135.0, 149.8, 153.9,
158.6; MS (EI) m/z 328 (65), 299 (45), 245 (100); [a]D20
1-Methoxy-3-(10,10-dimethylpentyl)-D8-THC(6d). Meth-
oxy cannabinoid 6d was prepared by the procedure
described above for the preparation of 6b. Methylation
of 2.80 g (8.17 mmol) of 7d20 gave 2.83 g (97%) of 6d as
1
a colorless oil: H NMR (300 MHz, CDCl3) d 0.83 (t,
J=7.1 Hz, 3H), 1.03–1.11 (m, 2H), 1.10 (s, 3H), 1.16–
1.29 (m, 2H), 1.25 (s, 6H), 1.38 (s, 3H), 1.51–1.60 (m,
2H), 1.70 (s, 3H), 1.73–1.90 (m, 3H), 2.05–2.12 (m, 1H),
2.66 (td, J=4.7, 10.8 Hz, 1H), 3.06 (dd, J=4.0 Hz, 1H),
3.81 (s, 3H), 5.41 (d, J=4.8 Hz, 1H), 6.38 (d, J=1.6 Hz,
1H), 6.43 (d, J=1.6 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) d 14.1, 18.4, 23.4, 23.5, 26.9, 27.6, 27.9, 28.8,
31.7, 36.2, 37.6, 44.3, 45.0, 55.1, 76.5, 100.7, 108.2,
111.6, 119.2, 135.0, 149.7, 153.9, 158.7; MS (EI) m/z 356
(45), 300 (100), 286 (25), 273 (30); HRMS calcd for
C24H36O2: 356.2716, found 356.2715; [a]2D0 ꢁ234ꢂ
(c=0.24, CHCl3).
1-Methoxy-3-(10,10-dimethylhexyl)-D8-THC(6e). Meth-
oxy cannabinoid 6e was prepared by the procedure
described above for the preparation of 6b. Methylation
of 2.59 g (7.26 mmol) of 7e20 gave 2.54 g (94%) of 6e as
1
a colorless oil: H NMR (300 MHz, CDCl3) d 0.83 (t,
J=7.1 Hz, 3H), 1.01–1.30 (m, 6H), 1.10 (s, 3H), 1.24 (s,
6H), 1.38 (s, 3H), 1.48–1.56 (m, 2H), 1.65–1.90 (m, 3H),
1.70 (s, 3H), 2.11–2.18 (m, 1H), 2.67 (td, J=4.7,
10.9 Hz, 1H), 3.15 (dd, J=4.1, 17.0 Hz, 1H), 3.81 (s,

J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
4125
3H), 5.41 (s, 1H), 6.38 (d, J=1.6 Hz, 1H), 6.42(d,
J=1.6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 14.1,
18.4, 22.5, 23.5, 24.3, 27.6, 27.7, 28.0, 28.8, 31.7, 32.6,
36.2, 37.7, 44.5, 45.1, 55.1, 76.4, 100.7, 108.3, 111.6,
119.2, 135.1, 149.7, 153.9, 158.7; MS (EI) m/z 370 (40),
300 (100), 287 (35); [a]2D0 ꢁ219ꢂ (c=0.21, CHCl3);
HRMS calcd for C25H38O2: 370.2871, found 370.2872.
13.1 Hz, 1H), 2.80 (dd, J=5.3, 17.5 Hz, 1H), 4.04 (d,
J=17.0 Hz, 1H), 4.08 (d, J=17.0 Hz, 1H), 5.77 (br. s,
1H), 6.84 (d, J=1.4 Hz, 1H), 6.92(dd, J=1.8, 8.2Hz,
1H), 7.17 (d, J=8.2Hz, 1H); 13C NMR (125.8 MHz,
CDCl3) d 19.3, 27.3, 27.8, 31.4, 31.9, 32.1, 34.4, 43.2,
66.9, 77.0, 114.2, 117.4, 121.7, 126.4, 122.4, 137.1, 150.9,
152.6; MS (EI) m/z 300 (100), 298 (42), 285 (36), 207
(51); [a]2D0 ꢁ103ꢂ (c=10.4, CHCl3); HRMS calcd for
C20H28O2: 300.2090, found 300.2089.
1-Deoxy-3-(10,10 -dimethylpropyl)-11-hydroxy-D8-THC
(9b). To a stirred suspension of 1.07 g (3.58 mmol) of
1-deoxycannabinoid 8b20 in 16 mL of ethanol at ambi-
ent temperature was added dropwise over 30 min a
solution of 0.96 g of SeO2 (8.73 mmol) in 17.6 mL of
ethanol/water (10:1). The reaction mixture was heated
at reflux for 18 h, filtered through a pad of Celite, which
was subsequently washed with three portions of metha-
nol, and the combined organic extracts were concentrated
in vacuo. The residue was extracted with three portions of
ether and the resulting ethereal solution was washed suc-
cessively with water then saturated NaHCO3. The organic
phase was dried (MgSO4) and concentrated in vacuo to
afford crude aldehyde 10b which was purified by dry
flash chromatography (ethyl acetate: petroleum ether,
9:1) to afford 0.96 g of 10b as a light brown oil which
was used without further purification.
1-Deoxy-3-(10,10 -dimethylbutyl)-11-hydroxy-D8-THC
(9c). 11-Hydroxycannabinoid 9c was prepared by the
procedure described above for the preparation of 9b.
Stepwise oxidation and reduction of 1.20 g (4.09 mmol)
of 8c20 gave 0.33 g (25% for two steps) of hydroxy can-
nabinoid 9c as a white foam: 1H NMR (500 MHz,
CDCl3) d 0.81 (t, J=7.4 Hz, 3H), 1.03–1.14 (m, 2H),
1.16 (s, 3H), 1.25 (s, 6H), 1.40 (s, 3H), 1.49–1.56 (m,
2H), 1.74 (td, J=5.0, 11.9 Hz, 1H), 1.82–1.90 (m, 1H),
1.91–2.02 (m, 2H), 2.23 (br. d, J=17.8 Hz, 1H), 2.68 (td,
J=5.5, 11.0 Hz, 1H), 2.80 (dd, J=5.0, 17.0 Hz, 1H),
4.04 (d, J=12.8 Hz, 1H), 4.08 (d, J=12.8 Hz, 1H), 5.75
(br. s, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.84 (dd, J=1.8,
8.2Hz, 1H), 7.13 (d, J=7.8 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3) d 14.7, 17.9, 19.1, 27.1, 27.6, 28.7,
28.8, 31.8, 32.0, 37.4, 43.0, 46.9, 66.8, 76.6, 114.6, 117.7,
121.5, 122.0, 126.0, 136.9, 149.5, 152.4; MS (EI) m/z 328
(46), 285 (100), 207 (60); [a]2D0 ꢁ153ꢂ (c=10.3, CHCl3);
HRMS calcd for C22H32O2: 328.2402, found 328.2402.
To a solution of 0.96 g (3.10 mmol) of the crude alde-
hyde in 35 mL of dry THF at 0 ꢂC under N2 was added
0.12g (3.07 mmol) of LiAlH 4. The reaction mixture was
allowed to warm to room temperature, stirred for 2h
and then quenched with aqueous NH4Cl. After filtering
through a pad of Celite, which was subsequently washed
with diethyl ether, the combined organic extracts were
dried (MgSO4) and concentrated in vacuo to afford the
crude product. Initial chromatography (gradient elution
with 17% diethyl ether to 35% diethyl ether in petro-
leum ether) gave a pale yellow resin which was further
purified by chromatography (gradient elution with 5%
acetone to 7% acetone in petroleum ether) to afford
1-Deoxy-3-(10,10 -dimethylpentyl)-11-hydroxy-D8-THC
(9d). Hydroxycannabinoid 9d was prepared by the pro-
cedure described above for the preparation of 9b. Step-
wise oxidation and reduction of 1.60 g (4.90 mmol) of
8d20 gave 0.48 g (28% for two steps) of hydroxy canna-
binoid 9d as a white foam: 1H NMR (500 MHz, CDCl3)
d 0.81 (t, J=7.3 Hz, 3H), 1.01–1.09 (m, 2H), 1.17 (s,
3H), 1.17–1.23 (m, 2H), 1.24 (s, 6H), 1.41 (s, 3H), 1.51–
1.57 (m, 2H), 1.76 (td, J=4.6, 11.4 Hz, 1H), 1.82–1.91
(m, 1H), 1.95–2.03 (m, 2H), 2.25 (dt, J=8, 17.9 Hz, 1H),
2.69 (dt, J=5.5, 11.4 Hz, 1H), 2.80 (dd, J=4.6, 16.5 Hz,
1H), 4.06 (d, J=12.8 Hz, 1H), 4.09 (d, J=12.8 Hz, 1H),
5.76 (br. s, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.84 (dd,
J=1.8, 7.8 Hz, 1H), 7.14 (d, J=8.2Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 14.2, 19.2, 23.5, 27.0, 27.3, 27.8,
29.0, 31.9, 32.1, 37.4, 43.1, 44.4, 67.1, 76.9, 114.8, 117.9,
121.8, 122.2, 126.2, 137.1, 149.8, 152.6; MS (EI) m/z 342
(33), 285 (100,), 269 (29), 255 (19); [a]2D0 +63ꢂ (c=14.3,
CHCl3); HRMS calcd for C23H34O2: 342.2562, found
342.2559;.
1
0.31 g (32% for two steps) of 9b as a white foam: H
NMR (500 MHz, CDCl3) d 0.69 (t, J=7.8 Hz, 3H), 1.17
(s, 3H), 1.24 (s, 6H), 1.40 (s, 3H), 1.60 (q, J=7.4 Hz,
1H), 1.72–2.02 (m, 5H), 2.20–2.28 (m, 1H), 2.69 (td,
J=5.5, 11.0 Hz, 1H), 2.80 (dd, J=4.2, 16.5 Hz, 1H),
4.05 (d, J=12.8 Hz, 1H), 4.08 (d, J=12.8 Hz, 1H), 5.76
(br. s, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.85 (dd, J=1.8,
7.8 Hz, 1H), 7.14 (dd, J=0.9, 8.2Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 9.34, 19.2, 27.3, 27.8, 28.5, 31.9,
32.1, 36.9, 37.7, 43.2, 67.0, 76.9, 114.9, 118.0, 121.7,
122.2, 126.2, 137.1, 149.4, 152.6; MS (EI) m/z 314 (59),
312 (20), 299 (13), 285 (100), 207 (100); [a]2D0 ꢁ126ꢂ
(c=9.0, CHCl3); HRMS calcd for C21H30O2: 314.2251,
found 314.2246.
1-Deoxy-3-(10,10 -dimethylhexyl)-11-hydroxy-D8-THC
(9e). 11-Hydroxycannabinoid 9e was prepared by the
procedure described above for the preparation of 9b.
Stepwise oxidation and reduction of 1.72g (5.05 mmol)
of 8e20 gave 0.231 g (13% for two steps) of hydroxy
1-Deoxy-3-(10,10 -dimethylethyl)-11-hydroxy-D8-THC
(9a). 11-Hydroxycannabinoid 9a was prepared by the
procedure described above for the preparation of 9b.
Stepwise oxidation and reduction of 1.27 g (4.46 mmol)
of 8a20 gave 0.35 g (26% for two steps) of hydroxy can-
nabinoid 9a as a white foam: 1H NMR (500 MHz,
CDCl3) d 1.17 (s, 3H), 1.29 (s, 9H), 1.41 (s, 3H), 1.76
(dt, J=5.8, 13.0 Hz, 1H), 1.80–1.90 (m, 1H), 1.94 (br. t,
J=13.0 Hz, 1H), 2.08–2.28 (m, 2H), 2.69 (dt, J=5.8,
1
cannabinoid 9e as a white foam: H NMR (500 MHz,
CDCl3) d 0.82(t, J=6.8 Hz, 3H), 1.03–1.12(m, 2H),
1.15–1.24 (m, 4H), 1.16 (s, 3H), 1.24 (s, 6H), 1.40 (s,
3H), 1.51–1.57 (m, 2H), 1.76 (td, J=4.6, 11.9 Hz, 1H),
1.81–2.03 (m, 3H), 2.23 (dt, J=8.0, 16.5 Hz, 1H), 2.69
(td, J=5.5, 11.0 Hz, 1H), 2.79 (dd, J=5.0, 17.0 Hz, 1H),
4.04 (d, J=12.8 Hz, 1H), 4.08 (d, J=12.8 Hz, 1H), 5.75

4126
J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
(br. s, 1H), 6.76 (d, J=2.3 Hz, 1H), 6.84 (dd, J=1.8,
8.2Hz, 1H), 7.13 (d, J=8.2Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 14.2, 19.2, 22.7, 24.5, 27.3, 27.8,
28.9, 29.0, 31.9, 32.1, 32.7, 37.5, 43.2, 44.6, 67.0, 77.2,
114.8, 117.9, 121.7, 122.2, 126.2, 137.1, 149.8, 152.6; MS
(EI) m/z 356 (32), 285 (100), 269 (18); [a]2D0 ꢁ144ꢂ
(c=6.5, CHCl3); HRMS calcd for C24H36O2: 356.2715,
found 356.2715.
J=4.6, 11.0 Hz, 1H), 3.31 (dd, J=4.6, 16.5 Hz, 1H),
3.80 (s, 3H), 4.03 (d, J=13.3 Hz, 1H), 4.06 (d,
J=13.3 Hz, 1H), 5.73 (d, J=4.6 Hz, 1H), 6.38 (d,
J=1.6 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 9.3, 18.5, 27.6, 27.7, 28.4, 31.6,
31.9, 36.9, 38.0, 45.3, 55.2, 67.2, 76.6, 100.8, 108.4,
111.3, 120.8, 138.6, 149.5, 154.0, 158.7, 158.7; MS (EI)
m/z 344 (29), 315 (24), 281 (28), 245 (64), 207 (100); [a]D20
ꢁ209ꢂ (c=0.46, CH2Cl2); HRMS calcd for C22H32O3:
344.2351, found 344.2351.
3-(10,10-Dimethylpropyl)-11-pivaloyloxy-D8-THC(13b).
To a solution of 0.507 g (2.81 mmol) of crude 2-methyl-
2-(3,5-dihydroxyphenyl)propane and 0.709 g (2.81 mmol)
of 4-hydroxymyrtenyl pivalate (12) in 188 mL of dry di-
chloromethane at ꢁ20 ꢂC was added dropwise with stir-
ring 1.94 mL (14.1 mmol) of boron trifluoride etherate.
The mixture was allowed to warm to 0 ꢂC and stirred for
2h, poured onto ice and neutralized with saturated
aqueous NaHCO3. After extraction with ether, the
combined organic extracts were dried (MgSO4) and
concentrated in vacuo to afford the crude product as a
dark brown foam. Chromatography (petroleum ether:-
ethyl acetate, 95:5) and subsequent recrystallization
(heptane:ethyl acetate, 95:5) afforded 0.233 g (20%) of
3-(10,10-Dimethylethyl)-11-pivaloyloxy-D8-THC(13a).
11-Pivaloyloxycannabinoid 13a was prepared by the
procedure described above for the preparation of 13b.
From 1.62g (9.76 mmol) of resorcinol 0.892g (23%) of
13a was obtained as a colorless oil following chromato-
graphy (petroleum ether/ether, 97.5:2.5 to 95:5): 1H
NMR (500 MHz, CDCl3) d 1.05 (s, 3H), 1.15 (s, 9H),
1.16 (s, 9H), 1.32 (s, 3H), 1.73–1.82 (m, 3H), 2.14–2.20
(m, 1H), 2.63 (td, J=4.6, 11.0 Hz, 1H), 3.30 (dd, J=4.2,
11.9 Hz, 1H), 4.43 (br. s, 2H), 5.35 (br. s, 1H), 5.68 (d,
J=4.6 Hz, 1H), 6.24 (d, J=1.8 Hz, 1H), 6.36 (d,
J=1.8 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) d 18.6,
27.3, 27.6, 27.7, 31.3, 31.4, 34.4, 39.0, 44.8, 68.3, 76.9,
105.1, 107.2, 109.9, 123.3, 133.9, 151.4, 154.5, 154.9,
178.9, 154.9.
pure 13b as white crystals, mp 214–215 ꢂC: H NMR
1
(300 MHz, CDCl3) d 0.67 (t, J=7.4 Hz, 3H), 1.10 (s,
3H), 1.18 (s, 6H), 1.20 (s, 9H), 1.38 (s, 3H), 1.56 (q,
J=7.3 Hz, 2H), 1.80–1.91 (m, 3H), 2.21–2.29 (m, 1H),
2.71 (td, J=4.6, 11.1 Hz, 1H), 3.36 (dd, J=3.9, 16.8 Hz,
1H), 4.48 (s, 2H), 5.20 (br. s, 1H), 5.73 (d, J=4.9 Hz,
1H), 6.21 (d, J=1.8 Hz, 1H), 6.37 (d, J=1.7 Hz, 1H);
13C NMR (75.5 MHz, CDCl3) d 9.2, 18.4, 27.2, 28.2,
31.2, 31.6, 36.8, 38.9, 44.8, 68.1, 76.5, 105.6, 107.8,
109.7, 123.2, 133.9, 149.7, 154.3, 154.7, 178.8; anal.
calcd for C26H38O4: C, 75.33; H, 9.24; found: C, 75.15;
H, 9.34.
1-Methoxy-3-(10,10 -dimethylethyl)-11-pivaloyloxy-D8-
THC. Methylation of 0.523 g (1.31 mmol) of 13a by the
procedure used for the preparation of 6b gave 0.447 g
(82%) of the corresponding methyl ether as a colorless
oil following chromatography (petroleum ether/ether,
97.5:2.5 to 95:5): 1H NMR (300 MHz, CDCl3) d 1.11 (s,
3H), 1.23 (s, 9H), 1.29 (s, 9H), 1.39 (s, 3H), 1.74–1.87
(m, 3H), 2.19–2.30 (m, 1H), 2.67 (td, J=4.5, 10.9 Hz,
1H), 3.31 (dd, J=3, 9, 16.9 Hz, 1H), 3.80 (s, 3H), 4.49
(br s, 2H), 5.75 (d, J=4.4 Hz, 1H), 6.44 (d, J=1.6 Hz,
1H), 6.49 (d, J=1.6 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) d 18.4, 27.2, 27.5, 27.7, 31.2, 31.4, 31.8, 39.0,
44.9, 55.0, 68.1, 76.3, 100.2, 107.6, 111.2, 123.4, 134.1,
149.9, 154.0, 158.7, 178.4.
1-Methoxy-3-(10,10 -dimethylpropyl)-11-pivaloyloxy-D8-
THC. Methylation of 0.556 g (1.34 mmol) of 13b by the
procedure used for the preparation of 6b gave 0.454 g
(79%) of the corresponding methyl ether as a colorless
oil following chromatography (petroleum ether:ether,
1
97.5:2.5 to 95:5): H NMR (300 MHz, CDCl3) d 0.70 (t,
J=7.4 Hz, 3H), 1.10 (s, 3H), 1.24 (s, 15H), 1.39 (s, 3H),
1.57 (q, J=7.7 Hz, 2H), 1.70–1.92 (m, 3H), 2.21–2.29
(m, 1H), 2.67 (td, J=4.6, 11.1 Hz, 1H), 3.30 (dd, J=3.9,
16.8 Hz, 1H), 3.79 (s, 3H), 4.49 (s, 2H), 5.76 (br. s, 1H),
6.38 (d, J=1.5 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H).
1-Methoxy-3-(10,10-dimethylethyl)-11-hydroxy-D8-THC
(11a). Reduction of 0.447 g (1.08 mmol) of the pivalate
ester by the procedure used for the preparation of 11b
gave 0.176 g (49%) of hydroxy cannabinoid 11a as a
1
colorless resin: H NMR (500 MHz, CDCl3) d 1.10 (s,
3H), 1.27 (s, 9H), 1.38 (s, 3H), 1.76–1.90 (m, 3H), 2.17–
2.24 (m, 1H), 2.65 (td, J=4.6, 11.0 Hz, 1H), 3.30 (dd,
J=4.6, 16.5 Hz, 1H), 3.80 (s, 3H), 4.02(d, J=13.3 Hz,
1H), 4.05 (d, J=13.3 Hz, 1H), 5.72(d, J=5.0 Hz, 1H),
6.43 (d, J=1.9 Hz, 1H), 6.48 (d, J=1.8 Hz, 1H); 13C
NMR (125.8 MHz, CDCl3) d 18.5, 27.7, 31.3, 31.5, 31.8,
34.8, 45.2, 55.2, 67.2, 76.6, 100.2, 107.6, 111.4, 120.8,
138.6, 151.1, 154.0, 158.8; MS (EI) m/z 330 (34), 299
(14), 231 (100), 207 (92); [a]2D0 ꢁ225ꢂ (c=1.08, CH2Cl2);
HRMS calcd for C21H30O3: 330.2194, found 330.2195.
1-Methoxy-3-(10,10-dimethylpropyl)-11-hydroxy-D8-THC
(11b). To a solution of 0.454 g (1.06 mmol) of pivalate
ester in 33 mL of dry THF under N2 at 0 ꢂC was added
0.051 g (1.34 mmol) of LiAlH4. The mixture was
allowed to warm to room temperature, stirred for 1 h
and quenched with 15 mL of aqueous NH4Cl. The
solids were filtered off through a pad of Celite, which
was subsequently washed with ether. The combined
organic fractions were dried (MgSO4) and concentrated
in vacuo to afford the crude product. Chromatography
(gradient elution, petroleum ether:acetone, 95:5 to 93:7)
3-(10,10-Dimethylbutyl)-1-methoxy-11-oxo-D8-THC(14c).
Selenium dioxide oxidation of 0.290 g (0.847 mmol) of
6c, using the procedure described above for the pre-
paration of 10b, gave, after chromatography (petroleum
ether/ethyl acetate, 9:1), 0.196 g (65%) of aldehyde as a
1
gave 0.233 g (68%) of pure 11b as a colorless resin: H
NMR (500 MHz, CDCl3) d 0.69 (t, J=7.3 Hz, 3H), 1.11
(s, 3H), 1.25 (s, 6H), 1.39 (s, 3H), 1.59 (q, J=7.4 Hz,
2H), 1.78–1.91 (m, 3H), 2.18–2.26 (m, 1H), 2.67 (td,

J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
4127
yellow solid: mp 109–110 ꢂC; 1H NMR (300 MHz,
CDCl3) d 0.82(t, J=7.2Hz, 3H), 1.03–1.13 (m, 2H),
1.10 (s, 3H), 1.25 (s, 6H), 1.43 (s, 3H), 1.50–1.55 (m,
2H), 1.79–1.93 (m. 2), 2.04–2.15 (m, 1H), 2.51–2.56 (m,
1H), 2.61 (td, J=4.5, 11.2Hz, 1H), 3.73 (dd, J=2.1,
17.9 Hz, 1H), 3 .82, (s, 3H), 6.39 (d, J=1.6 Hz, 1H), 6.42
(d, J=1.6 Hz, 1H), 6.83 (s, 1H), 9.50 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) d 14.8, 17.9, 18.2, 27.5, 28.7, 29.2,
30.8, 37.6, 44.9, 47.0, 55.1, 75.8, 100.7, 108.2, 110.2,
142.2, 148.9, 150.1, 153.7, 158.6, 193.7; MS (EI) m/z 356
(55), 306 (100).
2.20–2.25 (m, 1H), 2.66 (td, J=4.6, 10.9 Hz, 1H), 3.31
(dd, J=3.6, 17.1 Hz, 1H), 3.80 (s, 3H), 4.05 (s, 2H), 5.73
(d, J=4.2Hz, 1H), 6.37 (d, J=1.6 Hz, 1H), 6.42(d,
J=1.6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 14.1,
18.4, 23.4, 26.9, 27.6, 27.7, 28.8, 31.5, 31.8, 37.6, 44.2,
45.2, 67.1, 76.3, 100.6, 108.2, 111.1, 120.7, 138.5, 149.8,
153.8, 158.6; [a]D20 ꢁ284ꢂ (c=0.25, CHCl3); HRMS
calcd for C24H36O3: 372.2664, found 372.2663.
1-Methoxy -3- (10,10 -dimethylhexyl) - 11-oxo-D8 -THC
(14e). Selenium dioxide oxidation of 2.25 g (6.07 mmol)
of 6e, using the procedure described above for the pre-
paration of 10b gave 1.40 g (60%) of aldehyde 14e as an
orange solid, mp 117–119 ꢂC; 1H NMR (300 MHz,
CDCl3) d 0.83 (t, J=7.1 Hz, 3H), 1.02–1.30 (m, 6H),
1.10 (s, 3H), 1.25 (s, 6H), 1.43 (s, 3H), 1.51–1.56 (m,
2H), 1.80–1.93 (m, 2H), 2.05–2.18 (m, 1H), 2.49–2.56
(m, 1H), 2.62 (td, J=4.5, 11.2Hz, 1H), 3.73 (dd, J=4.1,
15.7 Hz, 1H), 3.82(s, 3H), 6.39 (d, J=1.6 Hz, 1H), 6.42
(d, J=1.6 Hz, 1H), 6.84 (br. s, 1H), 9.50 (s, 1H); 13C
NMR (75.5 MHz, CDCl3) d 14.1, 18.2, 22.5, 24.3, 27.5,
28.7, 28.8, 29.3, 30.9, 32.5, 37.7, 44.5, 44.9, 55.2, 75.8,
100.7, 108.1, 110.3, 142.5, 148.9, 150.2, 153.7, 158.7,
193.8; MS (EI) m/z 384 (20), 314 (100).
1-Methoxy-3-(10,10-dimethylbutyl)-11-hydroxy-D8-THC
(11c). To a suspension of 0.196 g (0.551 mmol) of alde-
hyde 14c in 3.5 mL of dry methanol was added sequen-
.
tially 0.205 g (0.551 mmol) of CeCl3 7H2O and 0.021 g
(0.551 mmol) of NaBH4. The reaction mixture was stir-
red at ambient temperature for 2h, the pH was adjusted
to 7.0 by the addition of 1M aqueous HCl. After pour-
ing into water the mixture was extracted with three
portions of CH2Cl2, dried (MgSO4) and the solvent was
removed in vacuo. The residue was purified by chroma-
tography (petroleum ether:ethyl acetate, 4:1) to give
0.185 g (94%) of cannabinoid 11c as a pale yellow gum:
1H NMR (500 MHz, CDCl3) d 0.82(t, J=7.1 Hz, 3H),
1.05–1.14 (m, 2H), 1.11 (s, 3H), 1.25 (s, 6H), 1.39 (s,
3H), 1.50–1.54 (m, 2H), 1.79–1.92 (m, 3H), 2.17–2.24
(m, 1H), 2.67 (td, J=4.6, 11.0 Hz, 1H), 3.31 (dd, J=4.6,
16.5 Hz, 1H), 3.80 (s, 3H), 4.05 (s, 2H), 5.73 (s, 1H),
6.38 (d, 1.6. 1H), 6.43 (d, J=1.6 Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 14.7, 17.9, 18.3, 27.5, 27.6, 28.7,
28.8, 31.4, 31.8, 37.6, 45.1, 46.9, 55.0, 66.8, 76.2, 100.5,
108.1, 111.1, 120.4, 138.4, 149.6, 153.8, 158.5; [a]D20
ꢁ238ꢂ (c=0.50, CHCl3); HRMS calcd for C23H34O3:
358.2508, found 358.2509.
1-Methoxy-3-(10,10-dimethylhexyl)-11-hydroxy-D8-THC
(11e). Luche reduction of 0.404 g (1.05 mmol) of alde-
hyde 14e by the procedure described above for the
reduction of 14c gave after chromatography (petroleum
ether/ethyl acetate, 4:1) 0.354 g (87%) of 11-hydroxy
cannabinoid 11e as a pale yellow oil: 1H NMR
(300 MHz, CDCl3) d 0.83 (t, J=7.3 Hz, 3H), 1.07–1.34
(m, 6H), 1.11 (s, 3H), 1.25 (s, 6H), 1.40 (s, 3H), 1.51–
1.58 (m, 2H), 1.78–1.88 (m, 3H), 2.21–2.25 (m, 1H), 2.67
(td, J=4.6, 10.9 Hz, 1H), 3.31 (dd, J=3.5, 17.2Hz, 1H),
3.81 (s, 3H), 4.06 (s, 2H), 5.73 (d, J=4.4 Hz, 1H), 6.38
(d, J=1.6 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3) d 14.1, 18.4, 22.6, 24.3, 27.6, 27.7,
28.8, 28.9, 31.5, 31.9, 32.6, 44.4, 45.2, 55.2, 67.2, 76.3,
100.7, 108.3, 111.2, 120.8, 138.6, 149.9, 154.0, 158.7;
HRMS calcd for C25H38O3: 386.2821, found 386.2818.
1-Methoxy-3-(10,10 -dimethylpentyl)-11-oxo-D8 -THC
(14d). Selenium dioxide oxidation of 2.00 g (5.17 mmol)
of 6d, using the procedure described above for the pre-
paration of 10b, gave, after chromatography (petroleum
ether/ethyl acetate, 87.5:12.5), 1.17 g (50%) of aldehyde
14d as a pale orange solid: 1H NMR (300 MHz, CDCl3)
d 0.83 (t, J=7.4 Hz, 3H), 1.02–1.09 (m, 2H), 1.14 (s,
3H), 1.18–1.28 (m, 2H), 1.25 (s, 6H), 1.43 (s, 3H), 1.52–
1.60 (m, 2H), 1.76–1.94 (m, 2H), 2.05–2.19 (m, 1H),
2.53–2.58 (m, 1H), 2.61 (td, J=4.5, 11.2Hz, 1H), 3.74
(dd, J=3.6, 16.1 Hz, 1H), 3.83 (s, 3H), 6.39 (d,
J=1.6 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H), 6.83–6.84 (m,
1H), 9.50 (s, 1H); 13C NMR (75 MHz, CDCl3) d 14.1,
18.2, 23.4, 26.9, 27.6, 28.7, 28.8, 29.2, 30.8, 37.9, 44.2,
45.0, 47.3, 55.1, 75.8, 100.7, 108.1, 110.2, 142.5, 148.9,
150.2, 153.7, 158.6, 193.8; MS (EI) m/z 370 (35), 314
(100), 300 (25).
3-(10,10 -Dimethylheptyl)-1-methoxy-11-oxo-D8 -THC
(14f). Selenium dioxide oxidation of 1.64 g (4.27 mmol)
of 4, using the procedure described above for the pre-
paration of 10b gave 1.12g (66%) of aldehyde 14f as an
orange solid: mp 118–119 ꢂC; Rf 0.31 (petroleum ether/
1
ethyl acetate, 94:6); H NMR (300 MHz, CDCl3) d 0.84
(t, J=6.9 Hz, 3H), 1.06–1.27 (m, 8H), 1.14 (s, 3H), 1.24
(s, 6H), 1.43 (s, 3H), 1.51–1.57 (m, 2H), 1.66–1.68 (m,
1H), 1.88 (td, J=4.1, 11.6 Hz, 1H), 2.07–2.18 (m, 1H),
2.51–2.57 (m, 1H), 2.61 (td, J=4.1, 11.2Hz, 1H), 3.73
(dd, J=4.5, 17.1 Hz, 1H), 3.81 (s, 3H), 6.39 (d,
J=1.6 Hz, 1H), 6.42(d, J=1.6 Hz, 1H), 6.83 (s, 1H),
9.50 (s, 1H); 13C NMR (75.5 MHz, CDCl3) d 14.1, 18.2,
22.6, 24.6, 27.5, 28.7, 28.9, 29.2, 30.0, 30.8, 31.7, 37.7,
44.5, 45.0, 55.1, 75.8, 100.7, 108.1, 110.2, 142.5, 148.9,
150.2, 153.7, 158.6, 193.8; MS (EI) m/z 398 (25), 314
(50), 281 (66), 207 (100).
1-Methoxy-3-(10,10-dimethylpentyl)-11-hydroxy-D8-THC
(11d). Luche reduction of 0.500 g (1.35 mmol) of alde-
hyde 14d by the procedure described above for the
reduction of 14c gave after chromatography (petroleum
ether/ethyl acetate, 4:1) 0.350 g (70%) of 11-hydroxy
cannabinoid 11d as a pale yellow gum: 1H NMR
(300 MHz, CDCl3) d 0.83 (t, J=7.3 Hz, 3H), 1.00–1.10
(m, 2H), 1.11 (s, 3H), 1.16–1.28 (m, 2H), 1.24 (s, 6H),
1.39 (s, 3H), 1.49–1.57 (m, 2H), 1.77–1.91 (m, 3H),
11-Hydroxy-3-(10,10-dimethylheptyl)-1-methoxy-D8-THC
(11f). Luche reduction of 0.314 g (0.789 mmol) of alde-
hyde 14f by the procedure described above for the

4128
J. W. Huffman et al. / Bioorg. Med. Chem. 10 (2002) 4119–4129
preparation of 14c gave after chromatography (petro-
leum ether/ethyl acetate, 85:15) 0.270 g (93%) of
11-hydroxy cannabinoid 11f as a pale yellow oil: Rf 0.30
(petroleum ether/ethyl acetate, 85:15); 1H NMR
(300 MHz, CDCl3) d 0.84 (t, J=6.9 Hz, 3H), 0.95–1.26
(m, 8H), 1.10 (s, 3H), 1.24 (s, 6H), 1.39 (s, 3H),
1.51–1.56 (m, 2H), 1.78–1.90 (m, 4H), 2.19–2.26 (m,
1H), 2.66 (td, J=4.1, 10.8 Hz, 1H), 3.30 (dd, J=3.3,
16.6 Hz, 1H), 3.79 (s, 3H), 4.03 (br s, 2H), 5.71 (s, 1H),
6.37 (d, J=1.6 Hz, 1H), 6.42(d, J=1.6 Hz, 1H); 13C
NMR (75.5 MHz, CDCl3) d 14.0, 18.3, 22.6, 24.5, 27.5,
27.6, 28.7, 28.8, 29.6, 29.9, 31.4, 31.7, 37.6, 44.4, 45.1,
55.0, 66.9, 76.3, 100.6, 108.2, 111.1, 120.5, 138.5, 149.7,
153.8, 158.6; [a]D20 ꢁ175ꢂ (c=0.3, CH2Cl2); HRMS calcd
for C26H40O3: 400.2977, found 400.2979.
sufficient volume of buffer C (50 mM Tris–HCl, 1 mM
EDTA, 3 mM MgCl2, and 5 mg/mL fatty acid free BSA,
pH 7.4) to bring the total volume to 0.5 mL. The addi-
tion of 1 mM unlabelled CP-55,940 was used to assess
nonspecific binding. Following incubation (30 ꢂC for
1 h), binding was terminated by the addition of 2mL of
ice cold buffer D (50 mM Tris–HCl, pH 7.4, plus 1 mg/
mL BSA) and rapid vacuum filtration through What-
man GF/C filters (pretreated with polyethyleneimine
(0.1%) for at least 2h). Tubes were rinsed with 2mL of
ice cold buffer D, which was also filtered, and the filters
subsequently rinsed twice with 4 mL of ice cold buffer
D. Before radioactivity was quantitated by liquid scin-
tillation spectrometry, filters were shaken for 1 h in 5mL
of scintillation fluid.
CP-55,940 and all cannabinoid analogues were prepared
by suspension in assay buffer from a 1 mg/mL ethanolic
stock without evaporation of the ethanol (final con-
centration of no more than 0.4%). When anandamide
was used as a displacing ligand, experiments were per-
formed in the presence of phenylmethylsulfonyl fluoride
(50 mM). Competition assays were conducted with 1 nM
[3H]CP-55,940 or 1 nM [3H]SR141716A and 6 con-
centrations (0.1 nM to 10 mM displacing ligands). Dis-
placement IC50 values were originally determined by
unweighted least-squares linear regression of log con-
centration-percent displacement data and then con-
verted to Ki values using the method of Cheng and
Prusoff.32
Receptor binding assays
1. CB1 assay. [3H]CP-55,940 (KD=690 nM) binding to
P2 membranes was conducted as described elsewhere,31
except whole brain (rather than cortex only) was used.
Displacement curves were generated by incubating
drugs with 1 nM of [3H]CP-55,940. The assays were
performed in triplicate, and the results represent the
combined data from three individual experiments.
2. CB2 assay. Human embryonic kidney 293 cells were
maintained in Dulbecco’s modified Eagle’s medium
(DMEM) with 10% fetal clone II (HyClone, Logan
UT) and 5% CO2 at 37 ꢂC in a Forma incubator. Cell
lines were created by transfection of CB2pcDNA3 into
293 cells by the Lipofectamine reagent (Life Technologies,
Gaithersburg, MD). The human CB2 cDNA was pro-
vided by Dr. Sean Munro (MRC, Cambridge, England).
Stable transformants were selected in growth medium
containing geneticin (1 mg/mL, reagent, Life Technolo-
gies, Gaithersburg, MD). Colonies of about 500 cells
were picked (about 2weeks post transfection) and
allowed to expand, then tested for expression of receptor
mRNA by northern blot analysis. Cell lines containing
moderate to high levels of receptor mRNA were tested
for receptor binding properties. Transfected cell lines
were maintained in DMEM with 10% fetal clone II plus
0.3–0.5 mg/mL geneticin and 5% CO2 at 37 ꢂC in a
Forma incubator.
Acknowledgements
The work at Clemson was supported by grant
DA03590, and that at Virginia Commonwealth Uni-
versity by grant DA03672(Billy R. Martin), both from
the National Institute on Drug Abuse.
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