Synthesis and pharmacology of 11-nor-1-methoxy-9- hydroxyhexahydrocannabinols and 11-nor-1-deoxy-9-hydroxyhexahydrocannabinols: New selective ligands for the cannabinoid CB2 receptor

Article abstract of DOI:10.1016/j.bmc.2005.11.023

Fourteen novel CB₂ receptor selective cannabinoids were synthesized via initial Lewis acid catalyzed rearrangement of resorcinol precursors to obtain the cannabinoid moiety. These are the 1-methoxy-9- hydroxyhexahydrocannabinols and the 1-deoxy

Full text of DOI:10.1016/j.bmc.2005.11.023

Bioorganic & Medicinal Chemistry 14 (2006) 2386–2397
Synthesis and pharmacology of
11-nor-1-methoxy-9-hydroxyhexahydrocannabinols and
11-nor-1-deoxy-9-hydroxyhexahydrocannabinols: New selective
ligands for the cannabinoid CB2 receptor
Karla-Sue C. Marriott,a John W. Huffman,a,* Jenny L. Wileyb and Billy R. Martinb
aHoward L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA
bDepartment of Pharmacology and Toxicology, Medical College of Virginia Campus,
Virginia Commonwealth University, Richmond, VA 23298-0613, USA
Received 5 October 2005; revised 9 November 2005; accepted 9 November 2005
Available online 29 November 2005
Abstract—Fourteen novel CB2 receptor selective cannabinoids were synthesized via initial Lewis acid catalyzed rearrangement of
resorcinol precursors to obtain the cannabinoid moiety. These are the 1-methoxy-9-hydroxyhexahydrocannabinols and the 1-de-
oxy-9-hydroxyhexahydrocannabinols, with 10,10-dimethylalkyl side chains of four to seven carbon atoms at C-3 of the cannab-
inoid nucleus. The cannabinols synthesized and described in this paper all exhibit greater affinity for the CB2 receptor than for
the CB1 receptor. Exceptionally high CB2 affinity was observed for 1-deoxy-9b-hydroxy-dimethylhexylhexahydrocannabinol
(JWH-361, 9, n = 3) Ki = 2.7 nM and 1-deoxy-9b-hydroxydimethylpentylhexahydrocannabinol (JWH-300, 9, n = 2) Ki = 5.3 nM.
In general, the stereochemistry of the 9-hydroxy group is important and the b-orientation enhances both CB2 receptor affinity
and selectivity.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Following the discovery of the CB1 and CB2 recep-
tors,4,5 there has been a resurgence of interest in the
medicinal chemistry and pharmacology of cannabi-
noids, which has resulted in significant advances in
The active components of Cannabis sativa (marijuana)
and their derivatives are classified as cannabinoids.
The most potent and abundant cannabinoid found in
the marijuana plant is D9-tetrahydrocannabinol (THC,
1), the structure of which was elucidated in 1964 by
Gaoni and Mechoulam.1 The medicinal value of mari-
juana has been known for centuries and its use almost
certainly predates documented history. THC exhibits a
diverse array of biological properties, including analge-
sic, anti-inflammatory, anti-emetic, anti-convulsive,
and anti-cancer effects. The behavioral effects of cannab-
inoids in humans and animals are complex, and the
mechanism(s) which elicits these effects has been the
subject of investigation for many years.2,3
11
CH
CH
2
3
9
8
7
10
OCH
3
OH
1
2
H C
3
H C
3
6
3
O
C H
9 19
O
CH
3
H C
3
H C
3
5
4
1
2
CH
CH OH
3
2
OCH
3
H C
3
H C
3
Keywords: Cannabinoids; Structure–activity relationships; CB2 can-
nabinoid receptors; Deoxycannabinoids.
O
C H
9
O
C H
9 19
19
H C
3
H C
3
*
Corresponding author. Tel.: +1 864 656 3133; fax: +1 864 656
6613; e-mail: huffman@clemson.edu
3
4
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.11.023

Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
2387
understanding the manner in which cannabinoids
interact with biological systems. The CB1 receptor is
found primarily in the central nervous system and
its activation is responsible for the psychotropic effects
of marijuana, whereas the CB2 receptor is almost
exclusively located in tissues of the immune system
such as the spleen, tonsil, and lymph nodes.6–8 The
CB2 receptor is known to participate in regulating im-
mune responses and/or inflammatory processes.9–15
However, at the molecular level there remain many
unanswered questions concerning the manner in which
cannabinoid receptor ligands interact with these
receptors.
(Table 1).18 Subsequently, several 1-deoxy-D8-THC
analogs were prepared and a number of them were
found to have significantly high selectivity for the CB2
receptor.20 The two most CB2 selective ligands in this
group are 3-(10,10-dimethylbutyl)-1-deoxy-D8-THC
(JWH-133, 6) and 3-(10,10-dimethylpropyl)-1-deoxy-D8-
THC (JWH-139, 7) with almost 200-fold and over
150-fold selectivity for the CB2 receptor, respectively
(Table 1).
OH
CH
3
R
H C
CH
CH
H C
Previous work reported by Felder et al. and Showalter
et al. determined that traditional cannabinoids such as
D9-THC (1) have comparable CB1 and CB2 receptor
affinities;16,17 however, 1-methoxy D9(11)-THC-DMH
(JWH-142, L759656, 2) and 1-methoxy-D8-THC-DMH
(JWH-143, L759633, 3) have high affinity for the CB2
receptor, but little affinity for the CB1 receptor (Table
1).18,19 In 1996, it was observed that some cannabinoids
lacking the characteristic hydroxyl group at C-1 have
high affinity for the CB2 receptor.18 1-Deoxy-11-hy-
droxy-D8-THC-DMH (deoxy-HU-210, JWH-051, 4)
was found to have very high affinity for the CB1 receptor
(Ki = 1.2 0.1 nM) and exceptionally high affinity for
the CB2 receptor (Ki = 0.032 0.019 nM, Table 1).
However, removal of the 11-hydroxy resulted in 3-
(10,10-dimethylheptyl)-1-deoxy-D8-THC (JWH-057, 5)
that was almost 10-fold selective for the CB2 receptor
3
3
3
CH
3
O
( )
n
O
R
H C
3
H C
3
3
5 R = C(CH ) (CH ) CH
6 R = C(CH ) (CH ) CH
7 R = C(CH ) CH CH
8 R = OCH
9 R = H
3 2
2 5
3
3
3
3 2
2 2
3 2
2
3
O
OH
R
R
H C
3
CH
CH
3
H C
3
CH
CH
3
CH
3
CH
O
( )
n
3
H C
3
O
( )
n
H C
3
3
3
10 R = OCH
11 R = H
12 R = H
13 R = OH
3
Table 1. Receptor affinities (means SEM) of 11-nor-9-hydroxyhexahydrocannabinols and related compounds
Compound
Ki (nM)
CB2
CB1
CB1/CB2
D9-THC (1)
41 2a
529 49c
924 104c
1.2 0.1d
23 7d
677 132c
2290 505c
7.9 0.9c
28 3c
36 10b
35 14c
1.1
15
1-Methoxy-3-(10,10-dimethylheptyl)-D9(11)-THC (JWH-142, 2)
1-Methoxy-3-(10,10-dimethylheptyl)D8-THC (JWH-143, 3)
65 8c
14
38
1-Deoxy-11-hydroxy-3-(10,10-dimethylheptyl)-D8-THC (JWH-051, 4)
3-(10,10-Dimethylheptyl)-1-deoxy-D8-THC (JWH-057, 5)
0.032 0.02d
2.9 1.6d
3.4 1.0c
14 10c
5.2 2.0c
23 7c
8
3-(10,10-Dimethylbutyl)-1-deoxy-D8-THC (JWH-133, 6)
199
164
1.5
1.2
4.1
6.6
14
3-(10,10-Dimethylpropyl)-1-deoxy-D8-THC (JWH-139, 7)
1-Deoxy-11-nor-9b-hydroxy-3-(10,10-dimethylheptyl)-HHC (JWH-102, 9, n = 4)
1-Deoxy-11-nor-9a-hydroxy-3-(10,10-dimethylheptyl)-HHC (JWH-103, 11, n = 4)
1-Methoxy-11-nor-9b-hydroxy-3-(10,10-dimethylbutyl)-HHC (JWH-298, 8, n = 1)
1-Methoxy-11-nor-9a-hydroxy-3-(10,10-dimethylbutyl)-HHC (JWH-277, 10, n = 1)
1-Methoxy-11-nor-9b-hydroxy-3-(10,10-dimethylpentyl)-HHC (JWH-299, 8, n = 2)
1-Methoxy-11-nor-9a-hydroxy-3-(10,10-dimethylpentyl)-HHC (JWH-278, 10, n = 2)
1-Methoxy-11-nor-9b-hydroxy-3-(10,10-dimethylhexyl)-HHC (JWH-350, 8, n = 3)
1-Methoxy-11-nor-9a-hydroxy-3-(10,10-dimethylhexyl)-HHC (JWH-349, 10, n = 3)
1-Methoxy-11-nor-9b-hydroxy-3-(10,10-dimethylheptyl)-HHC (JWH-341, 8, n = 4)
1-Methoxy-11-nor-9a-hydroxy-3-(10,10-dimethylheptyl)-HHC (JWH-340, 10, n = 4)
1-Deoxy-11-nor-9b-hydroxy-3-(10,10-dimethylbutyl)-HHC (JWH-310, 9, n = 1)
1-Deoxy-11-nor-9a-hydroxy-3-(10,10-dimethylbutyl)-HHC (JWH-336, 11, n = 1)
1-Deoxy-11-nor-9b-hydroxy-3-(10,10-dimethylpentyl)-HHC (JWH-300, 9, n = 2)
1-Deoxy-11-nor-9a-hydroxy-3-(10,10-dimethylpentyl)-HHC (JWH-301, 11, n = 2)
1-Deoxy-11-nor-9b-hydroxy-3-(10,10-dimethylhexyl)-HHC (JWH-361, 9, n = 3)
1-Deoxy-11-nor-9a-hydroxy-3-(10,10-dimethylhexyl)-HHC (JWH-362, 11, n = 3)
812 67
3905 91
415 50
906 80
395 20
198 23
589 65
30
69
12
38
2
6
1
4
13
33
376
100
135
1
8
6
10
10
10 0.1
30
36
1
3
4.5
29
1059 51
4589 367
118 16
153 15
5.3 0.1
30
22
295 64
48
2.7 0.1
34
4
6
23
63
127
3
8
5
3.8
a Ref. 27.
b Ref. 17.
c Ref. 20.
d Ref. 18.

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Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
benzene with apoverbenone.18,20 Although a similar
procedure could have been employed in the synthesis
of alcohols 9 and 11, a more efficient approach
employs cannabinoids 13, n = 1–4. These common
intermediates were then converted to the 1-methoxy
(8 and 10) and 1-deoxy-HHCs (9 and 11). We had
previously synthesized ketones similar to 11 using the
reaction of aryllithium reagents derived from 1,3-
dimethoxybenzene derivatives with apoverbenone.24,25
An alternative approach that is more amenable to
the synthesis of gram quantities of cannabinoids
13 (n = 1–4) is that of Tius et al.26 In this approach,
4-(2,6-dihydroxy-4-[10,10-dimethylalkyl]phenyl)-6,6-dim-
ethylbicyclo[3.1.1]heptan-2-ones (14, n = 1–4, Scheme
1) were prepared by the p-toluenesulfonic acid cata-
lyzed reaction of an appropriately substituted resorcin-
ol (15, n = 1–4) with the mixture of acetates and
apoverbenone obtained by oxidation of nopinone with
lead tetraacetate.26 Tetrahydrocannabinols 13, n = 1–4,
were obtained by stannic chloride mediated rearrange-
ment of 14.
Although structure–activity relationships (SAR) at the
CB1 receptor are reasonably well defined, those at the
CB2 receptor are not nearly as well understood.19,21
It is known, however, that in both the 1-methoxy-
and 1-deoxy-D8-THC series that a C-11 hydroxyl
group enhances affinity at both the CB1 and CB2
receptors.22 It is also known that in the 1-methoxy-
D8-THC series 10,10-dimethylalkyl side chains of five
to seven carbon atoms provide good affinity for the
CB2 receptor.20 In the 1-deoxy-D8-THC series
compounds with a 10,10-dimethylalkyl C-3 side chain
of two to seven carbon atoms all have high affinity
for the CB2 receptor. Also, 1-deoxy-20-methyl-D8-
THCs with C-3 alkyl chains of three to seven carbon
atoms have CB2 receptor affinities of less than
195 nM.23
In order to further develop SAR at the CB2 receptor
and to develop additional selective ligands for the
CB2 receptor, we have carried out the synthesis of
11-nor-1-methoxy- and 11-nor-1-deoxy-9b-hydroxyhex-
ahydrocannabinols (HHCs) with 10,10-dimethylbutyl to
10,10-dimethylheptyl C-3 side chains (8 and 9, n = 1–4).
The 9a-epimers (10 and 11, n = 1–4) were also prepared
to investigate the effect of stereochemistry at this center
upon both CB1 and CB2 receptor affinities. We had
previously reported the synthesis, CB1 and CB2 recep-
tor affinities for two of the 1-deoxy-9-hydroxy-11-nor-
hexahydrocannabinols (9 and 11, n = 4) and found
that both these dimethylheptyl analogs have high and
approximately equal affinity for both receptors. The
9b-hydroxy isomer has approximately 4-fold greater
receptor affinity than the a-epimer at both receptors
(Table 1).20
Cannabinoids 13 were converted to methoxy HHCs (8
and 10, n = 1–4) as shown in Scheme 2. Initial treat-
ment with methyl iodide and base gave methyl ethers
16, which upon reduction with lithium aluminum hy-
dride gave the equatorial b-alcohols (8, n = 1–4).
Stereoselective reduction with K-Selectride (potassium
tri-sec-butylborohydride) afforded the axial a-alcohols
(10, n = 1–4).
1-Deoxy-HHCs (9 and 11, n = 1–4) were prepared by
the method employed previously for the synthesis of
1-deoxycannabinoids (Scheme 3).20,22 Reaction of ke-
tones 13, n = 1–3, with sodium hydride and diethyl chlo-
rophosphate gave the corresponding phosphate esters.
Reduction with lithium in liquid ammonia removed
the phosphate ester and reduced the carbonyl group to
give the 9b-hydroxy-1-deoxycannabinoids (9, n = 1–3).
For the preparation of the 9a-hydroxy-1-deoxycannabi-
noids (11, n = 1–3), alcohols 9 were oxidized to the
corresponding ketones. Stereoselective reduction with
K-Selectride gave the 1-deoxy-9a-hydroxy-HHCs.
2. Results
In our previous work, epimeric alcohols 9 and 11,
n = 4, were prepared by reduction of the correspond-
ing ketone (deoxynabilone, 12, n = 4), which was in
turn prepared by the reaction of the aryllithium
derived from 2-bromo-5-(1,1-dimethylheptyl)methoxy-
O
OH
CH
OAc
AcO
H C
OAc
H C
3
+
OAc
+
3
+
H C
3
3
CH
3
HO
( )
n
CH
CH
CH
3
3
3
CH
3
15
O
OH
a
H C
3
b
13
CH
CH
CH
3
3
CH
3
HO
( )
n
3
14
Scheme 1. Reagents and conditions: (a) HOTs, CHCl3, 25 °C; (b) SnCl4, CHCl3, 25 °C.

Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
2389
OH
O
OCH3
CH3
OCH3
CH3
b
a
13
H3C
H3C
H3C
H3C
CH3
CH3
( )
O
( )
O
n
n
CH3
CH3
16
8
c
OH
OCH3
H3C
H3C
CH3
CH3
CH3
O
( )
n
10
Scheme 2. Reagents and conditions: (a) CH3I, K2CO3, acetone, reflux; (b) LiAlH4, THF, ꢀ78 °C; (c) K-Selectride, THF, ꢀ78 to ꢀ25 °C, then
NaOH, H2O2, EtOH.
OH
OH
a, b
c, d
13
H3C
H3C
CH3
CH3
H3C
H3C
CH3
CH3
CH3
( )
CH3
( )
O
n
O
n
9
11
Scheme 3. Reagents and conditions: (a) NaH/THF, 0 °C then (C2H5O)2P(O)Cl; (b) Li/NH3, THF, ꢀ78 °C; (c) CrO3, acetone, 0 °C; (d) K-Selectride,
THF, ꢀ78 to ꢀ25 °C, then NaOH, H2O2, EtOH.
The affinities of the 11-nor-1-methoxy- and 11-nor-1-
deoxyhexahydrocannabinols for 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.27 Affinities for the CB2 receptor were
determined by measuring the ability of the compounds
to displace [3H]CP-55,940 from a cloned human recep-
tor preparation using the procedure described by Show-
alter et al.17 The results of these determinations are
summarized in Table 1. Also included in Table 1 are
the receptor affinities for D9-THC (1), JWH-142 (2),
JWH-143 (3), JWH-051 (4), JWH-057 (5), JWH-133
(6), and JWH-139 (7) that were reported previously.
ity for the CB2 receptor with Ki < 70 nM. One of these
compounds, the 9b-hydroxy-3-(10,10-dimethylhexyl)-
HHC (JWH-350, 8, n = 3), shows excellent, 33-fold,
selectivity for the CB2 receptor with Ki = 12 1 nM at
the CB2 receptor and Ki = 395 20 nM at the CB1
receptor. The 9b-hydroxydimethylpentyl analog (JWH-
299, 8, n = 2) also has useful CB2 selectivity with
Ki = 30 2 nM at CB2 and Ki = 415 50 at the CB1
receptor.
With the exception of the 11-nor-1-deoxy-9-hydroxy-3-
(10,10-dimethylbutyl)-HHCs (JWH-310, 9 and JWH-
336, 11, n = 1), the 1-deoxy compounds have a signifi-
cantly higher affinity for the CB1 receptor than the cor-
responding 1-methoxy analogs. The 10,10-dimethylheptyl
analogs (JWH-102, 9 and JWH-103, 11, n = 4), which
we reported previously, both have very high affinity
for the CB1 receptor.20 The dimethylpentyl- and
dimethylhexyl-HHCs have modest CB1 receptor affini-
ties ranging from Ki = 63 3 nM for the 9b-hydrox-
ydimethylhexyl analog (JWH-361, 9, n = 3) to
Ki = 295 64 nM for the 9a-hydroxydimethylpentyl
compound (JWH-301, 11, n = 2). These 11-nor-1-de-
oxy-HHCs all have from high to modest affinity for
the CB2 receptor. The 9a-hydroxydimethylbutyl analog
(JWH-336, 11, n = 1) has the least affinity for the CB2
receptor with Ki = 153 15 nM. The other 1-deoxy ana-
logs all have Ki < 50 nM at the CB2 receptor. One of
With the exception of the dimethylheptyl analogs (JWH-
341, 8 and JWH-340 10, n = 4), none of the 1-methoxy-
9-hydroxy-HHCs (8 and 10, n = 1–3) has appreciable
affinity for the CB1 receptor, with Ki > 375 nM. The
dimethylheptyl compounds, JWH-341 and JWH-340,
have modest affinity for the CB1 receptor with
Ki = 100 8 nM for the 9b-isomer (JWH-341, 8, n = 4)
and Ki = 135 6 nM for the a-epimer (JWH-340, 10,
n = 4). All of these 1-methoxy-9-hydroxy-HHCs have
4- to 33-fold greater affinity for the CB2 receptor than
for the CB1 receptor. With the exception of the dim-
ethylbutyl analogs (JWH-298, 8 and, JWH-277, 10,
n = 1), all of the 1-methoxy HHCs have significant affin-

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Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
these compounds, the 9b-hydroxydimethylbutyl analog
(JWH-310, 9, n = 1), has 29-fold selectivity for the CB2
receptor with the desirable combination of high affinity
for the CB2 receptor, Ki = 36 3 nM, and little affinity
for the CB1 receptor, Ki = 1059 51 nM.
Ki = 7.9 0.9 nM, while the 9a-epimer has only slightly
less affinity with Ki = 28 3 nM. For both these com-
pounds the CB2 receptor affinities are only slightly high-
er than those at the CB1 receptor. For the 1-deoxy-10,10-
dimethylhexyl analogs, the 9b-isomer (JWH-361, 9,
n = 3) has moderate affinity for the CB1 receptor with
Ki = 63 3 nM and the 9a-alcohol (JWH-362, 11,
n = 3) has modest affinity, Ki = 127 8 nM. The 1-de-
oxy-9b-hydroxy-3-(10,10-dimethylpentyl)-HHC (JWH-
300, 9, n = 2) also has some affinity for the CB1 receptor
with Ki = 118 16 nM. However, the 9a-hydroxy-3-
(10,10-dimethylpentyl)-isomer (JWH-301, 11, n = 2) and
the 10,10-dimethylbutyl-HHCs (JWH-310, 9 and JWH-
336, 11, n = 1) have from slight to effectively no affinity
for the CB1 receptor with Ki = 295 64 nM for JWH-
301 to Ki = 4589 367 nM (JWH-336).
3. Discussion
In common with other 1-methoxy-D8-THCs lacking a
11-hydroxyl substituent, hexahydrocannabinols 8 and
10 (n = 1–3) have little affinity for the CB1 receptor with
Ki = 376–3905 nM (Table 1).19,21–23 The dimethylheptyl
analogs (8 and 10, n = 4) have considerably higher, but
still modest, affinity for this receptor. The equatorial
b-isomer (JWH-341, 8, n = 4) with Ki = 100 8 nM
has a slightly higher affinity for the CB1 receptor than
the axial a-epimer (JWH-340, 10, n = 4) with
Ki = 135 6 nM. These CB1 receptor affinities are inter-
mediate between those of the corresponding 1-methoxy-
and 11-hydroxy-1-methoxy-3-(10,10-dimethylalkyl)-D8-
THCs.21,22 It has been suggested that in a 1-deoxy-D8-
THC a cannabinoid 11-hydroxyl group may serve as a
surrogate for the phenolic 1-hydroxyl group in a
hydrogen bonding interaction with Lys 192 of the CB1
receptor.18 This effect is also seen in a series of 11-hy-
droxy-1-methoxy-D8-THCs.22 In the 1-methoxy-11-
nor-9-hydroxy-HHCs, this effect would appear to be
operative, but to a considerably lesser extent.
With the exception of 11-nor-9a-hydroxy-3-(10,10-dim-
ethylbutyl)-HHC
(JWH-336,
11,
n = 1)
with
Ki = 153 15 nM all the 1-deoxy compounds have from
good to very high affinity for the CB2 receptor. The
highest CB2 receptor affinity in this series is for the 9b-
hydroxy dimethylhexyl analog (JWH-361, 9, n = 3) with
Ki = 2.7 0.1 nM. The CB2 receptor affinities for the
other 1-deoxy-11-nor-9-hydroxy-3-(10,10-dimethylalkyl)-
HHCs range from Ki = 5.2 2 nM (JWH-102, 9, n = 4)
to Ki = 48 4 nM for the 9a-hydroxydimethylpentyl
analog (JWH-301, 11, n = 2). Although all of these 1-de-
oxy-HHCs have from 1.2- to 30-fold selectivity for the
CB2 receptor, the only one with the desirable properties
of high affinity for the CB2 receptor and little affinity for
the CB1 receptor is the 9b-hydroxy-3-(10,10-dimethylbu-
tyl) analog (JWH-310, 9, n = 1) with Ki = 1059 51 nM
at the CB1 receptor and Ki = 36 3 nM at the CB2
receptor. 1-Deoxy-11-nor-9b-hydroxy-3-(10,10-dimethyl-
pentyl)-HHC (JWH-300, 9, n = 2) has modest affinity,
Ki = 118 16 nM, for the CB1 receptor and very high
affinity for the CB2 receptor with Ki = 5.3 0.1 nM.
With the exception of the 10,10-dimethylbutyl analogs (8
and 10, n = 1) these 1-methoxy-HHCs all have from
moderate to high affinity for the CB2 receptor. The dim-
ethylhexyl and dimethylheptyl compounds (8 and 10,
n = 3 and 4) have similar high affinity for the CB2 recep-
tor. The 9b-(equatorial alcohols), JWH-350 (8, n = 3),
Ki = 12 1 nM, and JWH-341 (8, n = 4) with
Ki = 10 0.1 nM have somewhat greater affinity for
the CB2 receptor than the corresponding axial epimers.
For the 9a-(axial) isomers, the dimethylhexyl compound
(JWH-349, 10, n = 3) has Ki = 38 4 nM and the dim-
ethylheptyl analog (JWH-340, 10, n = 4) has
Ki = 30 1 nM. Three of these methoxy HHCs exhibit
good selectivity for the CB2 receptor with the combina-
tion of high affinity for the CB2 receptor and very weak
affinity for the CB1 receptor. One of these is JWH-350
(8, n = 3) with 33-fold affinity for the CB2 receptor.
For this compound Ki = 395 20 nM at CB1 and
Ki = 12 1 nM at the CB2 receptor. The other two
compounds, JWH-299 (8, n = 2) and JWH-349 (10,
n = 3), with 14- and 10-fold selectivity for the CB2 recep-
tor are considerably less selective than JWH-350. For
JWH-299 at the CB2 receptor Ki = 30 2 nM and at
the CB1 receptor Ki = 415 50 nM. At the CB2 receptor
With the exception of the 1-methoxy-11-nor-9-hydroxy-
3-(10,10-dimethylhexyl)-HHCs (JWH-350, 8 and JWH-
349, 10, n = 3) the CB1 receptor affinities of the equato-
rial 9b-alcohols are from somewhat to significantly high-
er than those of the axial 9a-alcohols. For the epimeric
1-methoxy-3-(10,10-dimethylhexyl) analogs (JWH-350
and JWH-349) the CB1 receptor affinities are identical.
The CB2 receptor affinities of the 9b-alcohols in both
the 1-methoxy and the 1-deoxy series are from slightly
more than 2-fold to more than 12-fold greater than
those of the axial 9a-alcohols.
A number of years ago, Reggio et al. carried out a com-
putational study that indicated a correlation between
the stereochemical orientation of substituents at C-9 of
the classical cannabinoid skeleton and the cannabinoid
activity of a compound.28 The results of this study indi-
cated that classical cannabinoid receptor ligands similar
to D9-THC (1) in which the substituent at C-9 was ori-
ented toward the bottom (a) face of the molecule had lit-
tle or no cannabinoid activity. The cannabinoid
activities cited by Reggio were based upon drug discrim-
ination studies in rhesus monkeys and were carried out
prior to the recognition of the existence of cannabinoid
JWH-349 has
Ki = 376 1 nM.
Ki = 38 4 nM
and
at
CB1
In the 1-deoxy series (9 and 11, n = 1–4), all these
compounds exhibit selectivity for the CB2 receptor,
however the previously reported 10,10-dimethylheptyl
compounds (JWH-102, 9 and JWH-103, 11, n = 4) have
quite high affinity for the CB1 receptor.20 The 9b-alcohol
(JWH-102) has very high CB1 receptor affinity with

Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
2391
receptor subtypes. Since the overt behavioral effects of
cannabinoids are considered to be mediated through
the CB1 receptor, it was probable that the conclusions
reached by Reggio et al. apply to that receptor. This
was verified subsequently by the synthesis and modeling
studies of the C-9 epimers of D7-THC. The 9b-methyl
isomer, in which the methyl group is directed above
the plane of the molecule, has Ki = 71.5 nM at the CB1
receptor and was somewhat less potent in vivo than
D9-THC29 (1). The 9a-epimer, in which the methyl
group is oriented behind the plane of the ring system,
has Ki = 304 nM and is much less potent in vivo. The
CB1 receptor affinities of the 1-methoxy- and 1-deoxy-
11-nor-9-hydroxy-HHCs in general follow the same
trend. Although the original observations regarding
the stereochemical orientation of the C-9 substituent
pertained to the CB1 receptor, the same trends are ob-
served at the CB2 receptor in the 11-nor-9-hydroxy-
HHC series.
matography was carried out on Sorbent Technologies
silica gel (32–63 lm) using the indicated solvents as
eluents. All new compounds were homogeneous to
TLC and 13C NMR. All target compounds were homo-
geneous to GLC or TLC in two different solvent
systems.
5.2. 11-Nor-3-(10,10-dimethylbutyl)-9-keto-hexahydro-
cannabinol (13, n = 1)
To a solution of 1.39 g (7.14 mmol) of dimethylbutyl res-
orcinol (15, n = 1) and 1.33 g (7.0 mmol) of p-TsOH in
75 mL of CHCl3 was added with stirring 1.52 g of the mix-
ture of acetates derived from the Pb(OAc)4 oxidation of
nopinone.26 The reaction mixture was stirred at ambient
temperature for 48 h, ether was added, and the resultant
solution was washed with 10% NaHCO3, water, dried
(MgSO4), and concentrated in vacuo to give 1.99 g
(95%) of 14, n = 1, as a brown paste. The unstable crude
product was used immediately without purification.
4. Conclusions
To a solution of 1.01 g (3.05 mmol) of 4-(2,6-dihydroxy-
4-[10,10-dimethylbutyl]-phenyl)-6,6-dimethylbicyclo[3.1.1]-
heptan-2-one (14, n = 1) in 70 mL CHCl3 was added
11 mL (11 mmol) of 1 M SnCl4 in CHCl3 with stirring
under an argon atmosphere. The reaction mixture was
stirred at room temperature for 21 h, poured onto
crushed ice, and extracted with ether. The organic ex-
tract was washed with 1 M aqueous HCl, water, 5%
aqueous NaHCO3, dried (MgSO4), and concentrated
in vacuo. The residue was chromatographed (hexanes/
ethyl acetate, 3:1) to give 0.475 g (47%) of 13, n = 1 as
Three of these 1-methoxy- and 1-deoxy-11-nor-9-hydro-
xy-3-(10,10-dimethlyalkyl)-hexahydrocannabinols
have
moderate 22- to 33-fold selectivity for the cannabinoid
CB2 receptor with the desirable combination of good
affinity for the CB2 receptor and little affinity for the
CB1 receptor. Two of these selective ligands are 1-deoxy
analogs, JWH-300 (9, n = 2) and JWH-310 (9, n = 1),
and one, JWH-350 (8, n = 3), is a 1-methoxy-HHC.
Although these compounds are selective for the CB2
receptor, they are not nearly as selective as JWH-133
(6), JWH-139 (7) or several 20-methyl-D8-THC ana-
logs.23 Two additional 1-methoxy analogs, JWH-299
(8, n = 2) and JWH-349 (10, n = 3), have some, 14- and
10-fold, selectivity, respectively, for the CB2 receptor.
These compounds were all synthesized from the corre-
sponding 11-nor-9-keto-3-(10,10-dimethylalkyl)-D8-hexa-
hydrocannabinols (14, n = 1–4). Hexahydrocannabinols
14 were synthesized by a variation of a procedure devel-
oped by Tius et al.26 In common with other cannabi-
noids, CB1 receptor affinity increased as the length of
the C-3 alkyl side chain increased from four to seven car-
bon atoms, and in general the 9b-hydroxy analogs had
somewhat greater affinity for both the CB1 and CB2
receptors than the 9a-epimers. This steric effect was
greater at the CB2 receptor than at the CB1 receptor.
1
a brown paste: H NMR (300 MHz, CDCl3) d 0.78–
0.82 (m, 4H), 1.02–1.28 (m, 2H), 1.12 (s, 3H), 1.20 (s,
6H), 1.50 (s, 3H), 1.50–1.60 (m, 2H), 1.90–2.01 (m,
1H), 2.15–2.19 (m, 2H), 2.47–2.54 (m, 1H), 2.61–2.67
(m, 1H), 2.86–2.94 (m, 1H), 4.14–4.17 (m, 1H), 6.35
(d, J = 1.6 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 7.92 (1H,
br s); 13C NMR (75 MHz, CDCl3) d 14.0, 17.9, 18.8,
26.8, 27.8, 28.6, 28.7, 34.7, 37.4, 40.8, 44.9, 46.8, 47.3,
76.6, 105.5, 106.9, 107.7, 150.7, 154.1, 155.0, 214.1.
5.3. 1-Methoxy-11-nor-3-(10,10-dimethylbutyl)-9-keto-
hexahydrocannabinol (16, n = 1)
To a solution of 0.079 g (0.239 mmol) of 13, n = 1 in
2.5 mL of dry acetone was added with stirring 0.265 g
K2CO3. The reaction mixture was stirred at ambient tem-
perature for 15 min and 0.1 mL (1.60 mmol) of iodome-
thane was added. The reaction mixture was stirred at
reflux under nitrogen for 6 h. The hot reaction mixture
was filtered, the residue was washed with hot acetone,
and the filtrate was dried (MgSO4) and concentrated in
vacuo to give 0.083 g (100%) of 16, n = 1, as a transparent
paste: 1H NMR (300 MHz, CDCl3) d 0.76–0.81 (m, 4H),
0.98–1.22 (m, 2H), 1.13 (s, 3H), 1.21 (s, 6H), 1.43 (s, 3H),
1.43–1.51 (m, 2H), 1.86–1.95 (m, 1H), 2.00–2.13 (m, 2H),
2.37–2.41 (m, 1H) 2.50–2.59 (m, 1H), 2.74–2.79 (m, 1H),
3.68–3.80 (m, 1H), 3.79 (s, 3H), 6.32–6.33 (d,
J = 1.7 Hz, 1H), 6.39–6.40 (d, J = 1.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 14.7, 18.7, 26.5, 27.7, 28.7,
31.0, 34.5, 37.7, 40.7, 45.7, 46.9, 47.4, 54.9, 76.6, 100.6,
108.0, 109.3, 150.4, 153.8, 158.1, 211.2.
5. Experimental
5.1. General
1H and 13C NMR spectra were recorded on a Bruker
300AC spectrometer. Mass spectral analyses were per-
formed on a Hewlett-Packard 5890A capillary gas chro-
matograph equipped with a mass sensitive detector.
HRMS data were obtained in the Mass Spectrometry
Laboratory, School of Chemical Sciences, University
of Illinois. Ether and THF were distilled from benzophe-
none ketyl immediately before use, and other solvents
were purified using standard procedures. Column chro-

2392
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5.4. 1-Methoxy-11-nor-3-(10,10-dimethylbutyl)-9b-hy-
droxy-hexahydrocannabinol (JWH-298, 8, n = 1)
was allowed to warm to room temperature and stirred
for 3 h. After dilution with ether, the resulting solution
was washed with 10% aqueous NaOH, and brine. After
drying (MgSO4), the solution was concentrated in vacuo
and the crude product was chromatographed (hexanes/
ethyl acetate, 3:1) to give 0.54 g (79%) of the phosphate
ester as a yellow oil that was used in the next step with-
To a solution of 0.097 g, (0.28 mmol) of 1-methoxy-11-
nor-3-(10,10-dimethylbutyl)-9-keto-hexahydrocannabinol
(16, n = 1) in 2 mL of dry THF was added with stirring
at ꢀ78 °C 0.029 g, (0.69 mmol) of 95% LiAlH4. The
reaction mixture was stirred overnight, quenched with
water, and extracted with ether. The organic extract
was washed with brine, dried (MgSO4), and concentrat-
ed in vacuo. The residue was chromatographed (hex-
anes/ethyl acetate, 3:1) to give 0.081 g (84%) of JWH-
298 as a light brown paste: 1H NMR (300 MHz, CDCl3)
d 0.79–0.84 (t, J = 7.2 Hz, 3H), 1.03–1.40 (m, 6H), 1.15
(s, 3H), 1.24 (s, 6H), 1.41 (s, 3H), 1.49–1.54 (m, 2H),
1.85–1.90 (m, 2H), 2.14–2.17 (br s, 1H), 2.39–2.47 (td,
J = 2.4, 11.2 Hz, 1H), 3.33–3.37 (m, 1H), 3.78 (s, 3H),
3.78–3.86 (m, 1H), 6.35–6.36 (d, J = 1.4 Hz, 1H), 6.40–
6.41 (d, J = 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 14.7, 17.9, 18.8, 26.0, 27.8, 28.6, 28.8, 33.5, 35.7,
37.7, 39.3, 46.9, 48.5, 54.9, 70.7, 76.6, 100.5, 108.1,
110.1, 149.7, 154.0, 158.3; MS(EI) m/z: 346 (32), 304
(100), 286 (24), 221 (15), 192 (28); HRMS: Calcd for
C22H34O3 346.2508. Found: 346.2508.
1
out further purification: H NMR (300 MHz, CDCl3) d
0.80–0.85 (m, 4H), 1.02–1.11 (m, 2H), 1.14 (s, 3H), 1.27
(s, 6H), 1.29–1.40 (m, 6H), 1.49 (s, 3H), 1.51–1.56 (m,
2H), 1.94–2.10 (m, 1H), 2.15–2.24 (m, 2H), 2.42–2.57
(m, 1H), 2.58–2.60 (m, 1H), 2.98–3.02 (m, 1H), 3.54–
3.61 (m, 1H), 4.17–4.27 (m, 4H), 6.65 (s, 1H), 6.84 (s,
1H); 13C NMR (75 MHz, CDCl3) d 14.4, 15.8, 15.9,
17.6, 26.3, 27.4, 28.2, 28.4, 34.2, 37.3, 40.3, 45.4, 46.4,
47.2, 64.3, 64.4, 76.6, 110.1, 111.8, 112.5, 112.6, 148.9,
150.4, 153.9, 209.3.
To a solution of 0.51 g lithium in 5 mL of liquid NH3 at
ꢀ78 °C was added 0.134 g (0.29 mmol) of the above
phosphate ester in 3 mL of dry THF and the reaction
mixture was stirred for 2 h. Excess lithium was quenched
with NH4Cl and the ammonia was allowed to evapo-
rate. The mixture was diluted with water, extracted with
ether, the organic extract was dried (MgSO4) and con-
centrated in vacuo. The residue was chromatographed
(hexanes/ethyl acetate, 4:1) to give 0.044 g (48%) of
JWH-310 as a white solid: 1H NMR (300 MHz, CDCl3)
d 0.79–0.83 (t, J = 7.1 Hz, 3H), 1.0–1.40 (m, 6H), 1.16 (s,
3H), 1.24 (s, 6H), 1.41 (s, 3H), 1.49–1.55 (m, 2H), 1.82
(m, 2H), 2.11–2.15 (m, 1H), 2.14–2.49 (m, 1H), 2.69–
2.73 (m, 1H), 3.77–3.84 (m, 1H), 6.74 (d, J = 1.9 Hz,
1H), 6.81–6.85 (dd, J = 1.9, 8.1 Hz, 1H), 7.09–7.12 (d,
J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.7,
17.9, 25.8, 28.1, 28.7, 28.8, 33.7, 35.3, 37.4, 39.7, 46.2,
46.9, 70.5, 76.6, 114.6, 117.5, 121.0, 125.1, 149.7,
152.7; MS(EI) m/z: 316 (33), 274 (32), 273 (100), 255
(8); HRMS: Calcd for C25H40O3 316.2402. Found:
316.2406.
5.5. 1-Methoxy-11-nor-3-(10,10-dimethylbutyl)-9a-
hydroxyhexahydrocannabinol (JWH-277, 10, n = 1)
To a solution of 0.083 g (0.24 mmol) of 1-methoxy-11-
nor-3-(10,10-dimethylbutyl)-9-keto-hexahydrocannabi-
nol (16, n = 1) in 2 mL of dry THF was added with stir-
ring at ꢀ78 °C 1 mL (1.0 mmol) of K-Selectride (1.0 M
in THF). The reaction mixture was allowed to warm
to room temperature and stirred overnight. After
quenching with 3 mL of water, 10 mL of ethanol,
4 mL of 1 M aqueous NaOH, and 4 mL of 30% H2O2
were added. After stirring for 20 min ,the mixture was
extracted with ether and the organic extract was washed
with brine, dried (MgSO4), and concentrated in vacuo.
The residue was chromatographed (hexane/ethyl ace-
tate, 3:1) to give 0.049 g (60%) of JWH-277 as a white
solid, mp 76–78 °C: 1H NMR (300 MHz, CDCl3) d
0.79–0.84 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.06–1.30
(m, 3H), 1.24 (s, 6H), 1.38 (s, 3H), 1.46–1.56 (m, 4H),
1.56–1.66 (m, 2H), 1.82 (br s, 1H), 1.93–1.98 (m, 1H),
2.87–2.91 (m, 1H), 3.16–3.21 (m, 1H), 3.79 (s, 3H),
4.23 (br s, 1H), 6.35 (d, J = 1.5 Hz, 1H), 6.40 (d,
J = 1.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.7,
17.9, 19.0, 22.6, 27.6, 28.7, 28.8, 29.0, 33.2, 37.2, 37.7,
46.9, 49.3, 55.1, 66.8, 76.6, 100.7, 108.2, 110.8, 149.5,
154.3, 158.4; MS(EI) m/z: 346 (31), 304 (100), 285 (43),
207 (24), 192 (26), 178 (16); HRMS: Calcd for
C22H34O3 346.2508. Found: 346.2504.
5.7. 1-Deoxy-11-nor-3-(10,10-dimethylbutyl)-9-keto-hexa-
hydrocannabinoid (12, n = 1)
A solution of 0.100 g (0.316 mmol) of 1-deoxy-11-nor-3-
(10,10-dimethylbutyl)-9b-hydroxy-hexahydrocannabinol
(9, n = 1) in the minimum volume of acetone was stirred
with cooling (ice bath) and JonesÕ reagent was added
dropwise until the reaction mixture maintained a dark
orange color. The reaction mixture was stirred for 4 h,
quenched with ethanol, and the resulting solution was
decanted. The green residue was washed twice with ace-
tone and the organic phases were combined. To this
mixture saturated aqueous NaHCO3 was added drop-
wise until the pH was neutral. Saturated brine was add-
ed and the reaction mixture was extracted with ether.
The extracts were dried (MgSO4) and concentrated in
vacuo. The crude product was purified by chromatogra-
phy (hexane/ethyl acetate, 3:1) to give 0.033 g (33%) of
12, n = 1, as a white solid: 1H NMR (300 MHz, CDCl3)
d 0.79–0.85 (t, J = 7 Hz, 3H), 1.01–1.23 (m, 3H), 1.17 (s,
3H), 1.25 (s, 6H), 1.48 (s, 3H), 1.49–1.58 (m, 2H), 1.88–
1.95 (m, 1H), 2.15–2.18 (m, 1H), 2.27–2.54 (m, 3H),
2.86–2.88 (m, 1H,), 3.05–3.12 (m, 1H,), 6.79–6.81 (d,
5.6. 1-Deoxy-11-nor-3-(10,10-dimethylbutyl)-9b-hydroxy-
hexahydrocannabinol (JWH-310, 9, n = 1)
To a solution of 0.49 (1.49 mmol) of 13, n = 1, in 5 mL
of dry THF under a nitrogen atmosphere at 0 °C was
added with stirring 0.080 g (2.0 mmol) of NaH (60% dis-
persion in oil). The reaction mixture was stirred at 0 °C
for 15 min and 0.43 mL (2.97 mmol) of diethyl chloro-
phosphate was added dropwise. The reaction mixture

Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
2393
J = 1.7 Hz, 1H), 6.84–6.88 (dd, J = 8.0, 1.8 Hz, 1H),
6.98–7.01 (d, J = 8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 14.8, 19.7, 26.6, 27.0, 28.5, 28.8, 35.4, 36.4,
40.3, 44.5, 45.8, 47.4, 77.1, 114.9, 118.0, 125.2, 150.1,
153.0, 213.0.
6H), 1.39 (s, 3H), 1.43–1.52 (m, 2H), 1.82–1.90 (m,
1H), 2.01–2.09 (m, 2H), 2.33–2.39 (m, 1H), 2.46–2.55
(m, 1H), 2.70–2.78 (m, 1H), 3.56–3.73 (m, 1H), 3.73 (s,
3H), 6.29 (s, 1H), 6.34–6.35 (d,J = 1.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 13.9, 18.6, 23.2, 26.5, 26.7,
27.7, 28.6, 28.7, 34.4, 37.5, 40.6, 44.0, 45.6, 47.3, 54.8,
76.4, 100.4, 108.0, 109.2, 150.3, 153.7, 158.0, 210.9.
5.8. 1-Deoxy-11-nor-3-(10,10-dimethylbutyl)-9a-hydroxy-
hexahydrocannabinol (JWH-336, 11, n = 1)
5.11. 1-Methoxy-11-nor-3-(10,10-dimethylpentyl)-9b-
hydroxyhexahydrocannabinol (JWH-299, 8, n = 2)
Deoxycannabinol 11, n = 1, was prepared from 1-deoxy-
11-nor-3-(10,10-dimethylbutyl)-9-keto-hexahydrocanna-
binoid (12, n = 1) by the procedure used to prepare
methoxy hexahydrocannabinol 10, n = 1. From 0.091 g
(0.29 mmol) of ketone 16, n = 1, there was obtained
after chromatography (hexanes/ethyl acetate, 3:1)
Methoxycannabinol 8, n = 2, was prepared by the meth-
od described above for the preparation of 8, n = 1. From
0.067 g (0.19 mmol) of 1-methoxy-11-nor-3-(10,10-dim-
ethylpentyl)-9-keto-hexahydrocannabinol (8, n = 2)
there was obtained after chromatography (hexanes/ethyl
acetate, 3:1) 0.068 g (71%) of JWH-299 as a colorless
gum: 1H NMR (300 MHz, CDCl3) d 0.81–0.85 (t,
J = 7.1 Hz, 3H), 1.03–1.40 (m, 8H), 1.12 (s, 3H), 1.21
(s, 6H), 1.38 (s, 3H), 1.50–1.56 (m, 2H), 1.82–1.87 (m,
2H), 2.13 (br s, 1H), 2.43–2.44 (m, 1H), 3.34–3.37 (m,
1H), 3.72–3.82 (m, 1H), 3.74 (s, 3H), 6.35–6.36 (d,
J = 1.5 Hz, 1H), 6.40–6.41 (d, J = 1.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 13.9, 18.8, 23.3, 25.5, 26.0,
26.8, 27.8, 28.7, 33.5, 35.7, 37.5, 39.3, 44.1, 48.5, 54.9,
70.6, 76.6, 100.5, 108.1, 110.1, 149.7, 154.0, 158.3;
MS(EI) m/z: 360 (38), 304 (100), 290 (33), 235 (16),
192 (19), 178 (15); HRMS: Calcd for C23H36O3
360.2664. Found: 360.2673.
1
0.067 g (73%) of JWH-336 as a pale brown paste: H
NMR (300 MHz, CDCl3) d 0.78–0.83 (t, J = 7.1 Hz,
3H), 1.02–1.13 (m, 3H), 1.20 (s, 3H), 1.24 (s, 6H), 1.40
(s, 3H), 1.44–1.57 (m, 4H), 1.61–1.64 (m, 2H), 1.83 (br
s, 1H), 1.91–1.96 (m, 1H), 2.50–2.55 (m, 1H), 2.80–
2.89 (m, 1H), 4.26–4.27 (m, 1H), 6.74 (d, J = 1.8 Hz,
1H), 6.79–6.83 (dd, J = 1.8, 8.1 Hz, 1H), 7.06–7.08 (d,
J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.7,
17.9, 20.2, 21.5, 27.8, 28.7, 28.8, 28.9, 32.7, 37.3, 37.3,
37.6, 47.0, 66.1, 76.6, 114.5, 117.3, 121.8, 125.1, 149.4,
152.9; MS(EI) m/z: 316 (43), 274 (40), 273 (100), 255
(51), 190 (13), 147 (13); HRMS: Calcd for C21H32O2
316.2402. Found: 316.2398.
5.9. 11-Nor-3-(10,10-dimethylpentyl)-9-keto-hexahydro-
cannabinol (13, n = 2)
5.12. 1-Methoxy-11-nor-3-(10,10-dimethylpentyl)-9a-
hydroxyhexahydrocannabinol (JWH-278, 10, n = 2)
Resorcinol 14, n = 2, was prepared by the method de-
scribed above for the preparation of 14, n = 1. From
1.38 g (6.63 mmol) of dimethylpentyl resorcinol (15,
n = 2) there was obtained 2.15 g (96%) of 14, n = 2, as
an unstable brown solid that was used without
purification.
Methoxy hexahydrocannabinol 10, n = 2, was prepared
by the method described above for the preparation of
10, n = 1. From 0.149 g (0.42 mmol) of 1-methoxy-11-
nor-3-(10,10-dimethylpentyl)-9-keto-hexahydrocannabinol
(16, n = 2) there was obtained after chromatography (hex-
anes/ethyl acetate, 3:1) 0.097 g (65%) of JWH-278 as a
1
Cannabinoid 13, n = 2, was prepared by the procedure
described above for the preparation of 13, n = 1. From
1.708 g (4.97 mmol) of 4-(2,6-dihydroxy-4-[10,10-dimeth-
ylpentyl]-phenyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one
(14, n = 2) there was obtained 0.654 g (38%) of 13, n = 2,
as a light brown transparent paste: 1H NMR (300 MHz,
CDCl3) d 0.79–0.85 (m, 4H), 1.05–1.21 (m, 4H), 1.14 (s,
3H), 1.21 (s, 6H), 1.48 (s, 3H), 1.50–1.62 (m, 2H), 1.90–
2.02 (m, 1H), 2.05–2.20 (m, 2H), 2.43–2.54 (m, 1H),
2.63–2.66 (m, 1H), 2.86–3.04 (m, 1H), 4.12–4.17 (m,
1H), 6.36 (s, 2H), 7.41 (br s, 1H); 13C NMR (75 MHz,
CDCl3) d 14.0, 18.9, 23.4, 26.9, 27.9, 28.7, 34.7, 37.3,
40.8, 44.1, 44.9, 47.4, 76.6, 105.5, 107.0, 150.8, 154.9,
213.5.
pale brown gum: H NMR (300 MHz, CDCl3) d 0.81–
0.86 (t, J = 7.1 Hz, 3H), 1.09 (s, 3H), 1.05–1.56 (m,
9H), 1.23 (s, 6H), 1.38 (s, 3H), 1.65–1.67 (m, 2H),
1.96–2.00 (m, 1H), 2.52 (br s, 1H), 2.87–2.93 (t,
J = 9.2 Hz, 1H), 3.17–3.23 (m, 1H), 3.78 (s, 3H), 4.38
(m, 1H), 6.35–6.42 (dd, J = 1.5, 17.8 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 14.0, 18.9, 20.6, 22.5, 23.3,
26.8, 27.5, 28.7, 29.0, 32.9, 37.0, 37.5, 44.2, 49.1, 55.0,
67.1, 76.6, 100.7, 108.2, 110.7, 149.6, 154.3, 158.3;
MS(EI) m/z: 360 (27), 304 (100), 285 (25), 207 (18),
192 (23), 178 (22), 57 (39); HRMS: Calcd for
C23H36O3 360.2664. Found: 360.2662.
5.13. 1-Deoxy-11-nor-3-(10,10-dimethylpentyl)-9b-
hydroxyhexahydrocannabinol (JWH-300, 9, n = 2)
5.10. 1-Methoxy-11-nor-3-(10,10-dimethylpentyl)-9-keto-
hexahydrocannabinol (16, n = 2)
Cannabinoid 13, n = 2, was converted to the phosphate
ester as described above for the preparation of the phos-
phate ester of 13, n = 1. From 0.100 g (0.291 mmol) 13,
n = 2 there was obtained 0.139 g (99%) of the phosphate
ester as a yellow oil following chromatography (hex-
anes/ethyl acetate, 3:1) that was used in the next step
without further purification: 1H NMR (300 MHz,
CDCl3) d 0.80–0.85 (m, 4H), 1.03–1.13 (m, 4H), 1.18
Methoxycannabinoid 16, n = 2, was prepared by the
procedure described above for the preparation of 16,
n = 1. From 0.150 g (0.436 mmol) of 13, n = 1, there
was obtained 0.149 g (95%) of 16, n = 2, as a pale yellow
1
transparent paste: H NMR (300 MHz, CDCl3) d 0.72–
0.77 (m, 4H), 0.92–1.00 (m, 4H), 1.08 (s, 3H), 1.16 (s,

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(s, 3H), 1.26 (s, 6H), 1.30–1.39 (m, 6H), 1.49 (s, 3H),
1.50–1.55 (m, 2H), 1.96–2.10 (m, 1H), 2.15–2.24 (m,
2H), 2.44–2.56 (m, 1H), 2.56–2.60 (m, 1H), 2.98–3.04
(m, 1H), 3.54–3.60 (m, 1H), 4.18–4.26 (m, 4H), 6.64 (s,
1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) d 13.9,
16.0, 16.1, 23.2, 26.5, 26.8, 27.6, 28.5, 34.4, 37.5, 40.5,
43.9, 45.7, 47.4, 64.5, 76.9, 110.4, 112.1, 113.0, 148.7,
150.8, 154.1, 209.6.
NMR (75 MHz, CDCl3) d 14.0, 20.2, 21.5, 23.3, 26.9,
27.8, 28.8, 28.9, 32.7, 37.2, 37.6, 44.2, 47.0, 66.1, 76.9,
114.5, 117.4, 121.8, 125.1, 149.5, 152.9; MS(EI) m/z:
330 (50), 274 (40), 273 (100), 255 (34), 213 (11), 147
(18), 57 (44), 55 (26); HRMS: Calcd for C22H34O2
330.2559. Found: 330.2560.
5.16. 11-Nor-3-(10,10-dimethylhexyl)-9-keto-hexahydro-
cannabinol (13, n = 3)
JWH-300 (9, n = 2) was prepared by reduction of the
phosphate ester as described above for the preparation
of 1-deoxy-11-nor-3-(10,10-dimethylbutyl)-9b-hydroxy-
hexahydrocannabinol (9, n = 1). From 0.150 g
(0.45 mmol) phosphate ester there was obtained after
chromatography (hexanes/ethyl acetate, 4:1) 0.042 g
(42%) of JWH-300 as an off-white solid: 1H NMR
(300 MHz, CDCl3) d 0.79–0.85 (t, J = 7 Hz, 3H), 1.0–
1.40 (m, 8H), 1.16 (s, 3H), 1.24 (s, 6H), 1.39 (s, 3H),
1.51–1.57 (m, 2H), 1.86–1.91 (m, 2H), 2.11–2.17 (m,
1H), 2.41–2.51 (td, J = 3.2, 11.6 Hz, 1H), 2.69–2.74 (m,
1H), 3.77–3.84 (m, 1H), 6.74–6.75 (d, J = 1.8 Hz, 1H),
6.82–6.85 (dd, J = 1.8, 8.1 Hz, 1H), 7.09–7.11 (d,
J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.0,
20.2, 23.3, 25.8, 26.9, 28.1, 28.8, 33.7, 35.3, 37.3, 39.7,
44.2, 46.2, 70.5, 77.0, 114.6, 117.5, 121.0, 125.1, 149.8,
152.7; MS(EI) m/z: 330 (43), 274 (33), 273 (100), 207
(15), 147 (17), 69 (26), 57 (36), 55 (30); HRMS: Calcd
for C22H34O3 330.2559. Found: 330.2564.
Resorcinol 14, n = 3, was prepared by the method de-
scribed above for the preparation of 14, n = 1. From
1.0 g (4.50 mmol) of dimethylpentyl resorcinol (15,
n = 3) there was obtained 1.53 g (95%) of 14, n = 3, as
an unstable brown solid that was used without
purification.
Cannabinoid 13, n = 3, was prepared by the procedure
described above for the preparation of 13, n = 1. From
2.13 g (5.95 mmol) of 4-(2,6-dihydroxy-4-[10,10-dim-
ethylhexyl]-phenyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one
(14, n = 3) there was obtained 0.86 g (41%) of 13, n = 3
as a brown paste: 1H NMR (300 MHz, CDCl3) d
0.80–0.85 (m, 4H), 1.04–1.20 (m, 6H), 1.16 (s, 3H),
1.20 (s, 6H), 1.50 (s, 3H), 1.52–1.63 (m, 2H), 1.90–2.00
(m, 1H), 2.04–2.22 (m, 2H), 2.45–2.54 (m, 1H), 2.64–
2.67 (m, 1H), 2.86–3.05 (m, 1H), 4.13–4.17 (m, 1H),
6.38 (s, 2H), 7.45 (br s, 1H); 13C NMR (75 MHz,
CDCl3) d 13.9, 18.9, 22.3, 23.4, 26.9, 27.9, 28.7, 34.7,
37.3, 40.6, 44.1, 44.8, 47.4, 76.8, 106.0, 107.0, 151.0,
155.0, 214.0.
5.14. 1-Deoxy-11-nor-3-(10,10-dimethylpentyl)-9-keto-
hexahydrocannabinol (12, n = 2)
Ketone 12, n = 2, was prepared by the procedure de-
scribed above for the preparation of 12, n = 1. Oxidation
of 0.100 g (0.303 mmol) of 9, n = 2, gave 0.035 g (35%)
of 12, n = 2 as a white solid following chromatography
(hexanes/ethyl acetate, 3:1): 1H NMR (300 MHz,
CDCl3) d 0.80–0.85 (t, J = 7.1 Hz, 3H), 1.02–1.25 (m,
5H), 1.18 (s, 3H), 1.24 (s, 6H), 1.47 (s, 3H), 1.47–1.57
(m, 2H), 1.87–1.96 (m, 1H), 2.15–2.17 (m, 1H), 2.28–
2.54 (m, 3H), 2.84–2.86 (m, 1H), 3.07–3.13 (m, 1H),
6.78–6.79 (d, J = 1.8 Hz, 1H), 6.84–6.87 (dd, J = 8.1,
1.8 Hz, 1H), 6.99–7.01 (d, J = 8.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 14.0, 19.9, 23.4, 26.9, 27.2, 28.2,
28.8, 35.8, 37.4, 40.8, 44.2, 45.8, 77.0, 114.8, 117.9,
125.1, 150.0, 153.0, 212.1.
5.17. 1-Methoxy-11-nor-3-(10,10-dimethylhexyl)-9-keto-
hexahydrocannabinol (16, n = 3)
Methoxy hexahydrocannabinol 16, n = 3, was prepared
by the procedure described above for the preparation
of 16, n = 1. From 0.346 g (0.966 mmol) of 13, n = 3,
there was obtained 0.257 g (72%) of 16, n = 3, as a trans-
1
parent paste: H NMR (300 MHz, CDCl3) d 0.75–0.85
(t, J = 7 Hz, 3H,), 1.0–1.45 (m, 7H), 1.15 (s, 3H), 1.24
(s, 6H) 1.5 (s, 3H), 1.52–1.60 (m, 3H), 1.86–2.20 (m,
3H), 2.35–2.70 (m, 2H), 2.75 (td, J = 3.6, 11.4 Hz, 1H)
3.80 (s, 3H), 6.37 (d, J = 1.8 Hz, 1H), 6.44 (d,
J = 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 13.9,
18.6, 22.3, 24.0, 26.8, 28.7, 29.1, 32.5, 34.6, 37.7, 40.8,
45.8, 47.5, 55.0, 76.6, 100.6, 108.2, 109.4, 150.5, 153.9,
158.2, 211.1.
5.15. 1-Deoxy-11-nor-3-(10,10-dimethylpentyl)-9a-
hydroxyhexahydrocannabinol (11, n = 2)
5.18. 1-Methoxy-11-nor-3-(10,10-dimethylhexyl)-9b-
hydroxyhexahydrocannabinol (JWH-350, 8, n = 3)
JWH 301 (11, n = 2) was prepared from 1-deoxy-11-
nor-3-(10,10-dimethylpentyl)-9-keto-hexahydrocannabi-
noid (12, n = 2) by the procedure employed for the prep-
aration of 11, n = 1 described above. From 0.057 g
(0.18 mmol) of 12, n = 2, there was obtained after chro-
matography (hexanes/ethyl acetate, 3:1) 0.047 g (82%) of
JWH-301 as a colorless paste: 1H NMR (300 MHz,
CDCl3) d 0.79–0.84 (t, J = 7.3 Hz, 3H), 0.99–1.13 (m,
3H), 1.18 (s, 3H), 1.24 (s, 6H), 1.41 (s, 3H), 1.45–1.56
(m, 6H), 1.61–1.64 (m, 2H), 1.74 (br s, 1H), 1.92–1.96
(m, 1H), 2.50–2.54 (m, 1H), 2.84–2.92 (m, 1H), 4.27
(m, 1H), 6.73–6.74 (d, J = 1.9 Hz, 1H), 6.80–6.83 (dd,
J = 1.7, 8.1 Hz, 1H), 7.07–7.09 (d, J = 8.0 Hz, 1H); 13C
JWH-350 (8, n = 3) was prepared from 1-methoxy-11-
nor-3-(10,10-dimethylhexyl)-9-keto-hexahydrocannabinol
(16, n = 3) by the procedure described above for the
preparation of 8, n = 1. From 0.131 g (0.35 mmol) of ke-
tone 16, n = 3, there was obtained after chromatography
(hexanes/ethyl acetate, 3:1) 0.098 g (75%) of JWH-350 as
1
a colorless gum: H NMR (300 MHz, CDCl3) d 0.80–
0.95 (t, J = 7 Hz, 3H), 1.05–1.38 (m, 10H), 1.13 (s,
3H), 1.25 (s, 6H), 1.40 (s, 3H), 1.50 (m, 2H), 1.73 (br
s, 1H), 1.85–1.95 (m, 1H), 2.15–2.25 (m, 1H), 2.40–
2.51 (td, J = 2.1, 11.1 Hz, 1H), 3.30–3.41 (m, 1H),

Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
2395
3.75–3.90 (m, 1H), 3.85 (s, 3H), 6.36–6.43 (d,
J = 14.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 14.1,
18.9, 22.5, 24.3, 26.1, 27.9, 28.8, 32.6, 33.6, 35.8, 37.7,
39.4, 44.4, 48.5, 55.0, 70.8, 77.0, 100.6, 108.2, 110.2,
149.9, 154.1, 158.4; MS(EI) m/z: 375 (37), 318 (15),
305 (20), 303 (22), 286 (10), 249 (10), 192 (12); HRMS:
Calcd for C24H38O3 374.2821. Found: 374.2821.
152.7; MS(EI) m/z: 344 (35), 274 (34), 273 (100), 271
(16); HRMS: Calcd for C23H36O2 344.2715. Found:
344.2710.
5.21. 1-Deoxy-11-nor-3-(10,10-dimethylhexyl)-9-keto-
hexahydrocannabinol (12, n = 3)
Ketone 12, n = 3, was prepared by the procedure de-
scribed above for the preparation of 12, n = 1. From
0.060 g (0.174 mmol) of 9, n = 3, there was obtained
0.035 g (59%) of 12, n = 3, as a white solid following
5.19. 1-Methoxy-11-nor-3-(10,10-dimethylhexyl)-9a-
hydroxyhexahydrocannabinol (JWH-349, 10, n = 3)
1
Alcohol 10, n = 3, JWH 349, was prepared from 1-meth-
oxy-11-nor-3-(10,10-dimethylpentyl)-9-keto-hexahydro-
cannabinol (16, n = 3) by the procedure used for the
preparation of 10, n = 1. From 0.135 g (0.36 mmol) of
16, n = 3, there was obtained after chromatography
(hexanes/ethyl acetate, 3:1) to give 0.096 g (71%) of
chromatography (hexanes/ethyl acetate, 3:1): H NMR
(300 MHz, CDCl3) d 0.81–0.85 (t, J = 7.1 Hz, 3H),
1.01–1.26 (m, 5H), 1.20 (s, 3H), 1.25 (s, 6H), 1.46 (s,
3H), 1.47–1.59 (m, 2H), 1.90–1.96 (m, 1H), 2.17–2.19
(m, 1H), 2.26–2.55 (m, 3H), 2.83–2.86 (m, 1H), 3.10–
3.15 (m, 1H), 6.75–6.78 (d, J = 1.8 Hz, 1H), 6.86–6.89
(dd, J = 8.1, 1.8 Hz, 1H), 7.00–7.02 (d, J = 8.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 13.9, 20.0, 22.3,
23.6, 26.6, 27.1, 28.3, 28.7, 35.6, 37.3, 40.8, 44.1, 46.4,
77.0, 115.1, 118.0, 125.2, 150.7, 153.0, 211.2.
1
JWH-349: H NMR (300 MHz, CDCl3) d 0.81–0.90 (t,
J = 7.1 Hz, 3H), 1.05–1.38 (m, 6H), 1.12 (s, 3H), 1.25
(s, 6H), 1.40 (s, 3H), 1.48–1.73 (m, 7H), 1.92–2.04 (m,
1H), 2.88–3.00 (m, 1H), 3.15–3.27 (m, 1H), 3.81 (s,
3H), 4.24 (br s, 1H), 6.36–6.43 (dd, J = 1.8, 16.2 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 14.1, 19.1, 22.5,
22.6, 24.3, 27.6, 28.8, 29.1, 36.6, 33.2, 37.3, 37.6, 44.4,
49.3, 55.1, 66.9, 76.6, 100.7, 108.3, 110.8, 149.7, 154.4,
158.4; MS(EI) m/z: 374 (32), 356 (12), 319 (14), 314
(16), 305 (22), 304 (100), 286 (30), 285 (24), 249 (16),
192 (19); HRMS: Calcd for C24H38O3 374.2821. Found:
374.2827.
5.22. 1-Deoxy-11-nor-3-(10,10-dimethylhexyl)-9a-
hydroxyhexahydrocannabinol (JWH-362, 11, n = 3)
JWH-362 was prepared from 1-deoxy-11-nor-3-(10,10-
dimethylhexyl)-9-keto-hexahydrocannabinoid
(12,
n = 3) by the method used for the synthesis of 11,
n = 1. From 0.035 g (0.10 mmol) of 12, n = 3, there
was obtained after chromatography (hexanes/ethyl ace-
tate, 3:1) 0.027 g (77%) of JWH-362 as a colorless
gum: 1H NMR (300 MHz, CDCl3) d 0.81–0.89 (t,
J = 6 Hz, 3H), 1.02–1.32 (m, 6H), 1.20 (s, 3H), 1.26 (s,
6H), 1.43 (s, 3H) 1.47–1.73 (m, 7H), 1.90–2.06 (m,
2H), 2.50–2.59 (m, 1H), 2.87–2.94 (m, 1H), 4.33 (s,
1H), 6.76 (d, J = 1.8 Hz, 1H), 6.82 (dd, J = 1.8, 8.1 Hz,
1H), 7.11 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 14.1, 20.2, 20.6, 21.6, 22.6, 24.4, 27.9, 28.8,
28.8, 29.0, 32.6, 37.3, 37.5, 44.5, 47.0, 66.5, 77.0, 114.6,
117.5, 121.8, 125.2, 149.6, 152.9; MS(EI) m/z: 345 (15),
344 (59), 283 (11), 274 (43), 273 (100), 255 (32); HRMS:
Calcd for C23H36O2 344.2715. Found: 344.2716.
5.20. 1-Deoxy-11-nor-3-(10,10-dimethylhexyl)-9b-
hydroxyhexahydrocannabinol (JWH-361, 9, n = 3)
Cannabinoid 13, n = 3, was converted to the phosphate
ester by the procedure described above for the prepara-
tion of 9, n = 1. From 0.195 g (0.545 mmol) 13, n = 3,
there was obtained 0.186 g (69%) of phosphate ester as
a yellow oil following chromatography (hexanes/ethyl
1
acetate, 3:2): H NMR (300 MHz, CDCl3) d 0.81–0.85
(m, 4H), 1.00–1.14 (m, 6H), 1.19 (s, 3H), 1.25 (s, 6H),
1.27–1.39 (m, 6H), 1.48 (s, 3H), 1.50–1.54 (m, 2H),
1.97–2.10 (m, 1H), 2.16–2.25 (m, 2H), 2.45–2.55 (m,
1H), 2.56–2.61 (m, 1H), 2.98–3.03 (m, 1H), 3.54–3.61
(m, 1H), 4.17–4.26 (m, 4H), 6.65 (s, 1H), 6.83 (s, 1H);
13C NMR (75 MHz, CDCl3) d 13.9, 16.1, 16.3, 22.2,
24.6, 25.9, 26.8, 27.9, 28.5, 34.5, 37.3, 40.9, 43.8, 45.5,
47.2, 64.2, 76.9, 110.2, 112.1, 113.1, 147.7, 151.0,
154.4, 209.7.
5.23. 11-Nor-3-(10,10-dimethylheptyl)-9-keto-hexahydro-
cannabinol (13, n = 4)
Resorcinol 14, n = 4, was prepared by the method de-
scribed above for the preparation of 14, n = 1. From
4.30 g (18.2 mmol) of dimethylpentyl resorcinol (15,
n = 4), there was obtained 6.26 g (92%) of 14, n = 4, as
an unstable brown solid that was used without
purification.
The phosphate ester was reduced to JWH-361 by the
procedure employed for the synthesis of 9, n = 1. From
0.186 g (0.38 mmol) of phosphate ester there was ob-
tained after chromatography (hexanes/ethyl acetate,
3:2) 0.068 g (53%) of JWH-361 as a white solid: 1H
NMR (300 MHz, CDCl3) d 0.80–0.90 (t, J = 7.1 Hz,
3H), 1.0–1.39 (m, 10H), 1.16 (s, 3H), 1.26 (s, 6H), 1.43
(s, 3H), 1.49–1.60 (m, 2H), 1.76 (br s, 1H), 1.86–1.94
(m, 1H), 2.14–2.19 (m, 1H), 2.45–2.55 (m, 1H), 2.70–
2.79 (m, 1H), 3.76–3.89 (m, 1H), 6.77 (s, 1H), 6.82–
6.90 (d, J = 8.1 Hz, 1H), 7.10–7.17 (d, J = 7.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 14.1, 20.2, 22.6, 24.4,
25.8, 28.2, 28.8, 28.9, 32.6, 33.8, 35.4, 37.4, 39.8, 44.5,
46.2, 70.6, 77.0, 114.6, 117.5, 121.1, 125.1, 149.8,
Cannabinoid 13, n = 4, was prepared by the procedure
described above for the preparation of 13, n = 1. From
3.83 g (11.32 mmol) of 4-(2,6-dihydroxy-4-[10,10-dimeth-
ylheptyl]-phenyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one
(14, n = 4) there was obtained 1.62 g (42%) of 13, n = 4,
as a transparent brown paste: 1H NMR (300 MHz,
CDCl3) d 0.81–0.86 (m, 4H), 1.0–1.3 (m, 8H), 1.13 (s,
3H), 1.20 (s, 6H), 1.50 (s, 3H), 1.50–1.60 (m, 2H),
1.89–2.02 (m, 1H), 2.10–2.20 (m, 2H), 2.47–2.51 (m,

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1H), 2.63–2.67 (m, 1H), 2.87–2.90 (m, 1H), 4.14–4.19
(m, 1H), 6.35–6.39 (d, J = 11 Hz, 2H), 7.88 (br s, 1H);
13C NMR (75 MHz, CDCl3) d 14.0, 18.8, 22.6, 24.5,
26.8, 27.8, 28.6, 29.9, 31.7, 34.7, 37.2, 40.7, 44.3, 44.9,
47.3, 76.6, 105.5, 106.8, 107.6, 150.7, 154.1, 155.1, 214.7.
(15), 318 (15), 305 (21), 304 (100), 303 (16), 285 (19),
263 (11), 192 (11); HRMS: Calcd for C25H40O3
388.2977. Found: 388.2982.
5.26.1. CB1 assay. [3H]CP-55,940 (KD = 690 nM) bind-
ing to P2 membranes was conducted as described else-
where,30 except whole brain (rather than cortex only)
was used. Displacement curves were generated by
incubating drugs with 1 nM [3H]CP-55,940. The
assays were performed in triplicate, and the results
represent the combined data from three individual
experiments.
5.24. 1-Methoxy-11-nor-3-(10,10-dimethylheptyl)-9-keto-
hexahydrocannabinol (16, n = 4)
Cannabinoid 16, n = 4, was prepared by the procedure
described above for the preparation of 16, n = 1. From
0.129 g (0.347 mmol) of 13, n = 4, there was obtained
0.095 g (71%) of 16, n = 4, as a pale yellow transparent
paste: 1H NMR (300 MHz, CDCl3) d 0.75–0.90 (m,
4H), 1.0–1.4 (m, 8H), 1.15 (s, 3H), 1.25 (s, 6H), 1.55
(s, 3H), 1.50–1.70 (m, 2H), 1.90–2.20 (m, 3H), 2.30–
2.65 (m, 2H), 2.80–2.90 (td, J = 3.6, 12 Hz, 1H), 3.80
(m, 1H), 3.85 (s, 3H), 6.38 (s, 1H), 6.44 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 14.1, 18.8, 22.7, 24.6, 26.7,
27.9, 28.8, 30.0, 31.8, 34.6, 37.8, 40.8, 44.4, 45.8, 47.5,
55.0, 76.6, 100.6, 108.2, 109.3, 150.6, 153.9, 158.2, 211.3.
5.26.2. CB2 assay. Human embryonic kidney 293 cells
were maintained in DulbeccoÕs modified EagleÕs medium
(DMEM) with 10% fetal clone II (HyClone, Logan UT)
and 5% CO2 at 37 °C 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 2 weeks post transfection) and al-
lowed to expand, and 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 °C in a Forma incubator.
5.25. 1-Methoxy-11-nor-3-(10,10-dimethylheptyl)-9b-
hydroxyhexahydrocannabinol (JWH-341, 8, n = 4)
JWH-341 was prepared from 1-methoxy-11-nor-3-(10,10-
dimethylheptyl)-9-keto-hexahydrocannabinol (16, n = 4)
by the procedure described above for the synthesis of 8,
n = 1. From 0.095 g (0.25 mmol) of 16, n = 4, there was
obtained after chromatography (hexanes/ethyl acetate,
1
3:1) 0.090 g (97%) JWH-341 as a pale brown gum: H
NMR (300 MHz, CDCl3) d 0.83–0.92 (t, J = 6 Hz,
3H), 1.0–1.42 (m, 12H), 1.10 (s, 3H), 1.25 (s, 6H), 1.41
(s, 3H), 1.55–1.60 (m, 2H), 1.66 (br s, 1H), 1.85–1.94
(m, 1H), 2.14–2.26 (m, 1H), 2.40–2.50 (td, J = 2.4,
11.1 Hz, 1H), 3.30–3.44 (m, 1H), 3.80 (m, 1H), 3.81 (s,
3H), 6.37–6.43 (dd, J = 1.8, 14 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 14.1, 18.9, 22.7, 24.6, 26.1, 27.9,
28.8, 29.7, 30.0, 31.8, 33.6, 35.8, 37.7, 39.4, 44.5, 48.5,
55.0, 70.8, 77.0, 100.6, 108.2, 110.1, 149.9, 154.1,
158.4; MS(EI) m/z: 389 (11), 388 (41), 346 (12), 332
(17), 305 (23), 304 (100), 303 (24), 286 (12), 263 (10),
192 (12); HRMS: Calcd for C25H40O3 388.2977. Found:
388.2982.
The current assay is a modification of Compton and co-
workers.17,31 Cells were harvested in phosphate-buffered
saline containing 1 mM EDTA and centrifuged at 500g.
The cell pellet was homogenized in 10 mL of solution A
(50 mM Tris–HCl, 320 mM sucrose, 2 mM EDTA, and
5 mM MgCl2, pH 7.4). The homogenate was centrifuged
at 1600g (10 min), the supernatant saved, and the pellet
washed three times in solution A with subsequent centri-
fugation. The combined supernatants were centrifuged
at 100,000g (60 min). The (P2 membrane) pellet was
resuspended in 3 mL buffer B (50 mM Tris–HCl,
1 mM EDTA, and 3 mM MgCl2, pH 7.4) to yield a pro-
tein concentration of approximately 1 mg/mL. The tis-
sue preparation was divided into equal aliquots, frozen
on dry ice, and stored at ꢀ70 °C. Binding was initiated
by the addition of 40–50 lg membrane protein to silan-
ized tubes containing [3H]CP-55,940 (102.9 Ci/mmol)
and a 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 addition of 1 lM unlabelled CP-55,940 was used
to assess nonspecific binding. Following incubation
(30 °C for 1 h), binding was terminated by the addition
of 2 mL ice-cold buffer D (50 mM Tris–HCl, pH 7.4,
plus 1 mg/mL BSA) and rapid vacuum filtration
through Whatman GF/C filters (pretreated with poly-
ethyleneimine (0.1%) for at least 2 h). Tubes were rinsed
with 2 mL ice-cold buffer D, which was also filtered, and
the filters were subsequently rinsed twice with 4 mL ice-
cold buffer D. Before radioactivity was quantitated by
5.26. 1-Methoxy-11-nor-3-(10,10-dimethylheptyl)-9a-
hydroxyhexahydrocannabinol (JWH-340, 10, n = 4)
JWH-340 was prepared from 1-methoxy-11-nor-3-(10,10-
dimethylpentyl)-9-keto-hexahydrocannabinol (16, n = 4)
by the procedure employed for the synthesis of 10, n = 1.
From 0.071 g (0.18 mmol) of 16, n = 4, there was ob-
tained after chromatography (hexanes/ethyl acetate,
3:1) 0.044 g (62%) JWH-340 as a colorless gum: 1H
NMR (300 MHz, CDCl3) d 0.82–0.93 (t, J = 7 Hz,
3H), 1.03–1.38 (m, 12H), 1.21 (s, 3H), 1.25 (s, 6H),
1.40 (s, 3H), 1.47–1.82 (m, 4H), 1.95–1.99 (m, 1H),
2.85–2.97 (m, 1H), 3.15–3.25 (m, 1H), 3.80 (s, 3H),
4.24 (m, 1H), 6.36–6.43 (dd, J = 1.8, 16.8 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 14.1, 19.1, 22.6, 22.7, 24.6,
27.6, 28.8, 29.1, 30.0, 31.8, 33.2, 37.3, 37.7, 44.5, 49.3,
55.1, 66.9, 77.0, 100.7, 108.3, 110.8, 149.7, 154.4,
158.4; MS(EI) m/z: 389 (12), 388 (45), 370 (12), 332

Karla-Sue C. Marriott et al. / Bioorg. Med. Chem. 14 (2006) 2386–2397
2397
11. Malan, T. P.; Ibrahim, M. M.; Vanderah, T. W.; Mak-
riyannis, A.; Porreca, F. Chem. Phys. Lipids 2002, 121,
191.
liquid scintillation spectrometry, filters were shaken for
1 h in 5 mL of scintillation fluid.
12. Malan, T. P.; Ibrahim, M. M.; Deng, H.; Liu, Q.; Main,
H. P.; Vanderah, T.; Porreca, F.; Makriyannis, A. Pain
2001, 93, 239.
13. Ibrahim, M. M.; Deng, H.; Zvonok, A.; Cockayne, D. A.;
Kwan, J.; Mata, H. P.; Vanderah, T. W.; Lal, J.; Porreca,
F.; Makriyannis, A. M.; Malan, T. P. Proc. Natl. Acad.
Sci. U.S.A. 2003, 100, 10529.
14. Zhang, J.; Hoffert, C.; Vu, H. K.; Groblewski, T.; Ahmad,
S.; OÕDonnell, D. Eur. J. Neurosci. 2003, 2750.
15. Kehl, L. J.; Hamamoto, D. T.; Wacnik, P. W.; Croft, D.
L.; Norsted, B. D.; Wilcox, G. L.; Simone, D. A. Pain
2003, 103, 175.
16. Felder, C. F.; Joyce, K. E.; Briley, E. M.; Mansouri, J.;
Mackie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L.
Mol. Pharmacol. 1995, 48, 443.
17. Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood,
M. E. J. Pharmacol. Exp. Ther. 1996, 278, 989.
18. Huffman, J. W.; Yu, S.; Showalter, V.; Abood, M. E.;
Wiley, J. L.; Compton, D. R.; Martin, B. R.; Reggio, P. H.
J. Med. Chem. 1996, 39, 3875.
19. Huffman, J. W. Mini Rev. Med. Chem. 2005, 5, 641.
20. Huffman, J. W.; Liddle, J.; Yu, S.; Aung, M. M.; Abood,
M. E.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem.
1999, 7, 2905.
21. Huffman, J. W. Curr. Pharm. Des. 2000, 6, 1323.
22. Huffman, J. W.; Bushell, S. M.; Miller, J. R. A.; Wiley, J.
L.; Martin, B. R. Bioorg. Med. Chem. 2002, 10, 411.
23. Huffman, J. W.; Bushell, S. M.; Joshi, S. N.; Wiley, J. L.;
Martin, B. R. Bioorg. Med. Chem. 2006, 14, 247.
24. Huffman, J. W.; Zhang, X.; Wu, M.-J.; Joyner, H. H.;
Pennington, W. T. J. Org. Chem. 1991, 56, 1482.
25. Huffman, J. W.; Joyner, H. H.; Lee, M. D.; Pennington,
W. T. J. Org. Chem. 1991, 56, 2082.
CP-55,940 and all cannabinoid analogs were prepared
by suspension in assay buffer from a 1 mg/mL ethano-
lic stock without evaporation of the ethanol (final
concentration of not more than 0.4%). Competition
assays were conducted with 1 nM [3H]CP-55,940 and
six concentrations (0.1 nM to 10 lM displacing
ligands). Displacement IC50 values were originally
determined by unweighted least-squares linear regres-
sion of log concentration-percent displacement data
and then converted to Ki values using the method of
Cheng and Prusoff.32
Acknowledgments
The work at Clemson University was supported by
Grants DA03590 and DA15340, and that at Virginia
Commonwealth University by Grant DA03672, all from
the National Institute on Drug Abuse.
References and notes
1. Gaoni, Y.; Mechoulam, R. J. Am. Chem. Soc. 2001, 86,
1646.
2. Hollister, L. E. Pharmacol. Rev. 1986, 38, 1.
3. Dewey, W. L. Pharmacol. Rev. 1986, 38, 151–178.
4. Devane, W. A.; Dysarz, F. A.; Johnson, M. R.;
Melvin, L. S.; Howlett, A. C. Mol. Pharmacol. 1988,
34, 605–613.
5. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993,
365, 61–65.
26. Tius, M. A.; Kawakami, J. K.; Hill, W. G. A.; Makri-
yannis, A. Mol. Pharmacol. 1991, 40, 656.
6. Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.;
Casellas, W. A.; Devane, W. A.; Felder, C. C.;
Herekenham, M.; Mackie, K.; Martin, B. R.; Mechou-
lam, R.; Pertwee, R. G. Pharmacol. Rev. 2002, 54,
161–202.
27. Compton, D. R.; Rice, K. C.; DeCosta, B. R.; Razdan, R.
K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R.
J. Pharmacol. Exp. Ther. 1993, 265, 218.
28. Reggio, P. H.; Greer, K. V.; Cox, S. M. J. Med. Chem.
1989, 32, 1630.
7. Klein, T. W.; Friedman, H.; Specter, S. J. Neuroimmunol.
1998, 83, 102.
8. Buckley, N. E.; McCoy, K. L.; Mezey, E.; Bonner, T.;
Zimmer, A.; Felder, C. C.; Glass, M.; Zimmer, A. Eur. J.
Pharmacol. 2000, 396, 141.
9. Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Golden-
berg, D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.;
Mechoulam, R.; Fride, E. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 14228.
10. Conti, S.; Costa, B.; Colleoni, M.; Parolaro, D.; Giagnoni,
G. Br. J. Pharmacol. 2002, 135, 181.
29. Huffman, J. W.; Banner, W. K.; Zoorob, G. K.; Joyner,
H. H.; Reggio, P. H.; Martin, B. R.; Compton, D. R.
Tetrahedron 1995, 51, 1017.
30. Martin, B. R.; Compton, D. R.; Thomas, B. F.; Prescott,
W. R.; Little, P. J.; Razdan, R. K.; Johnson, M. R.;
Melvin, L. S.; Mechoulam, R.; Ward, S. J. Pharmacol.
Biochem. Behav. 1991, 40, 471.
31. Little, P. J.; Compton, D. R.; Johnson, M. R.; Melvin, L.
S.; Martin, B. R. J. Pharmacol. Exp. Ther. 1988, 247, 1046.
32. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973,
22, 3099.