Unsaturated side chain β-11-hydroxyhexahydrocannabinol analogs

Article abstract of DOI:10.1021/jm950934b

The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)- apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the β-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (K(i) = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-β-11- hydroxyhexahydrocannabinol was the least potent binding to CB1 (K(i) = 8.9 nM) and had the lowest selectivity between CB1 and CB2.

Full text of DOI:10.1021/jm950934b

3790
J . Med. Chem. 1996, 39, 3790-3796
Un sa tu r a ted Sid e Ch a in â-11-Hyd r oxyh exa h yd r oca n n a bin ol An a logs
J akob Busch-Petersen,† W. Adam Hill,‡ Pusheng Fan,‡ Atmaram Khanolkar,‡ Xuang-Qun Xie,§
Marcus A. Tius,*,† and Alexandros Makriyannis*,‡,
Department of Chemistry, University of Hawaii, 2545 The Mall, Honolulu, Hawaii 96822, and School of Pharmacy, Institute of
Material Science, and Molecular Cell Biology, University of Connecticut, 372 Fairfield Road, Storrs, Connecticut 06269
Received December 22, 1995X
The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with
their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain,
we synthesized a series of cannabinoids in which rotation around the C1′-C2′ bond is blocked.
The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-
apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific
introduction of the â-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity
for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki ) 0.89
nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-
â-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki ) 8.9 nM) and had
the lowest selectivity between CB1 and CB2.
In tr od u ction
The search for cannabinoids possessing a high degree
of pharmacological potency and selectivity has led to the
synthesis and testing of a large number of novel analogs
from which structure-activity relationships (SAR) could
be established.1 A review of the existing literature
recognized four pharmacophores on the cannabinoid
structure which can be associated with cannabimimetic
activity.2 These include a phenolic hydroxyl and an
aliphatic side chain attached to the phenolic ring, both
of which are present in the natural tetrahydrocannab-
inol constituents found in Cannabis. Additionally,
structural modification of the basic cannabinoid proto-
types identified two further pharmacophores: a north-
ern aliphatic hydroxyl at the 9- or 11-position of the
classical and nonclassical cannabinoids and a southern
aliphatic hydroxyl found in the nonclassical cannab-
inoids as exemplified by CP-55,940.
F igu r e 1. Target compounds used to examine the effects of
sterically constraining the side chain of classical cannabinoids.
The importance of the aliphatic side chain was first
compound 1 could be partially hydrogenated to provide
2; double bond isomerization would then provide 3; full
reduction of 1 would provide 4.
demonstrated by Adams,3 who showed that by substi-
tuting the n-pentyl chain of ∆9-THC with a 1′,1′-
dimethylheptyl chain led to a 100-fold increase in
In the absence of a bulky group at the benzylic
potency. While the structure-activity of various sub-
position of the side chain, Archer’s procedure5 for
stitutions of the aliphatic alkyl chain have revealed
coupling of resorcinol and terpenic fragments cannot be
something with regard to the nature of the pharma-
used; nonregiospecific coupling takes place, and yields
cophoric requirements in this region, the alkyl chain is
are <50%. Consequently, the cuprate approach making
flexible and therefore could achieve any one of a number
use of apoverbenone which has been developed in our
of conformations. We therefore decided to constrain the
group was brought to bear on the problem.6
alkyl side chain by introducing unsaturation at the 1′-
Commercially available 3,5-dimethoxybenzoic acid (5)
position.4 We also limited the length of the alkyl chain
was converted to methyl ketone 6 by treatment with
to seven carbons to optimize the structure-activity
information that could be gleaned from imposing rota-
tional constraints on the first three carbon atoms
attached to the 3-position of 11-hydroxyhexahydrocan-
methyllithium (Scheme 1).7 Alkyne 7 was obtained via
the enol phosphate.8 Deprotonation of 7 with methyl-
lithium, followed by addition on n-amyl bromide in
dimethyl sulfoxide (DMSO), led to 8.9 Methyl ether
nabinol.
cleavage with BBr3 was successful; however, rapid
quenching of the reaction with aqueous NaHCO3 and
ice was necessary in order to suppress the formation of
byproducts. The air-sensitive resorcinol product was
immediately protected as bis(ethoxyethyl) species 9 (EE
) 2-ethoxyethyl). The overall yield of 9 from 8 was 84%.
Lithiation of 9 at C2 and formation of the higher-order
cuprate, followed by addition of the BF3‚Et2O complex
of (+)-apoverbenone, gave 10. The reaction did not
Syn th esis
The synthetic plan called for the preparation of the
four compounds shown in Figure 1. The acetylenic
† University of Hawaii.
‡ School of Pharmacy.
§ Institute of Material Science.
Molecular Cell Biology.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(95)00934-4 CCC: $12.00 © 1996 American Chemical Society

Unsaturated Side Chain Hydroxyhexahydrocannabinols
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3791
Sch em e 1. Synthesis of the Acetylenic Protected Resorcinol 9 Used as the Starting Resorcinol for Coupling to
(+)-Apoverbenonea
a
(a) 4 equiv of CH3Li, 20 equiv of (H3C)3SiCl, H3O+, 79%; (b) LDA, (EtO)2P(O)Cl, LDA, 91%; (c) CH3Li, n-C5H11Br, DMSO, 72%; (d)
BBr3, CH2Cl2, 91%; (e) H2CCHOCH2CH3, p-TSA, 92%.
Sch em e 2. Synthesis of 3-Hept-1-ynyl-11-hydroxyhexahydrocannabinola
a
(a) n-BuLi, THF, 0 °C, LiCuCN(imidazolide), -78 °C, (+)-apoverbenone, BF3‚Et2O; (b) p-TsOH, CH3OH, 25 °C, 55% (two steps); (c)
TMSOTf, CH3NO2, 5 °C, 89%; (d) t-Bu(CH3)2SiCl, imidazole, DMF, 25 °C, 92%; (e) H3COCHPPh3, PhH, 70 °C, 1.5 h; (f) Cl3CCO2H,
CH2Cl2(H2O), 25 °C; (g) K2CO3, EtOH, 25 °C, 85% (three steps); (h) NaBH4, EtOH, 0 °C; (i) n-Bu4NF, THF, 0 °C, 95% (two steps).
proceed to completion. Nevertheless, hydrolytic cleav-
age of the phenolic protecting groups produced 11, which
was highly crystalline and could be isolated in 50-60%
overall yield from 9. In an attempt to improve the
efficiency of this transformation, Lipshutz’ newer tech-
nique was tried, in which imidazole is used in place of
thiophene.10 The yield of 11 was 40-55%, and unre-
acted 9 was easily recovered and recycled. Based on
recovered starting material, the yield of 11 was 67%.
Exposure of 11 to catalytic amounts of trifluo-
romethanesulfonic (triflic) acid in dry nitromethane
resulted in a clean and fast (4-6 h) reaction leading to
12. This reaction was difficult to reproduce on larger
scale. A clean, rapid, and reproducible process resulted
when trimethylsilyl triflate was used in place of triflic
acid, indicating that the reaction is inhibited by traces
of water. Whether triflic acid or trimethylsilyl triflate
is the catalytically active species is not clear.
the strongly shielded axial proton is the furthest upfield
signal at 0.75 ppm, while the equatorial proton appears
at 3.25 ppm. The hydroxymethylene protons on C11
showed an interesting concentration dependency. In
dilute solution they appear as a simple doublet in the
1H-NMR spectrum, but at higher concentration the
signal changed into a doublet of doublets. This is
probably due to decreased rotation around the C9-C11
bond which may result from stacking of the molecules.
An alternative approach for the introduction of C11
was also examined (eq 1).13 Exposure of 13 to the lithio
anion of chloromethyltrimethylsilane led to diastereo-
meric epoxides 16, along with unreacted 13. The use of
The free phenolic hydroxyl in 12 was protected as the
tert-butyldimethylsilyl (TBS) ether. Treatment of 13
with (methoxymethylene)triphenylphosphorane in ben-
zene11 produced a mixture of methyl enol ethers which
were hydrolyzed to aldehyde diastereoisomers 14 and
15.12 Epimerization gave equatorial aldehyde 15 in 85%
overall yield from 13. Carbonyl reduction and desily-
lation led to 1 in 95% yield. HMQC, HMBC, and NOE
correlations established the powerful anisotropic effects
excess reagent, or the addition of an aliquot during the
reaction, had no effect upon the yield, which indicated
that competing enolization was taking place. Exposure
of 16 to catalytic BF3‚Et2O led to a ca. 9/1 mixture of
aldehydes 14 and 15.14 Epimerization as described
above led to 15 in 79% overall yield. Although the
Wittig process was more useful for accessing 15, this
1
affecting the protons at C10. In the H-NMR spectrum

3792 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Busch-Petersen et al.
approach makes it possible to selectively prepare the
thermodynamically less stable R-hydroxymethyl series.
Partial hydrogenation of 1 using Lindlar’s catalyst in
the presence of quinoline15 was a slow process which
produced (Z)-alkene 2 in 72% isolated yield, along with
approximately 13% of unreacted 1, an equal amount of
the fully saturated compound, and traces of (E)-alkene
3. A pure sample of 2 was isolated by HPLC. The
isomerization of 2 to 3 was accomplished with thiophe-
nol and catalytic 1,1′-azobis(cyclohexanecarbonitrile)
(ACN) in refluxing benzene.16
The difficulties which were encountered during the
partial hydrogenation of 1 were surprising since the
process had been carried out successfully with 8 as a
model. In striking contrast to 1, partial hydrogenation
of 8 proceeded in a highly selective manner, leading to
the (Z)-alkene in 93% yield. The difference in reactivity
between 1 and 8 may be due in part to differences in
molecular shape which in the case of 1 preclude certain
geometries for approach to the catalyst surface. Finally,
the catalytic hydrogenation of 1 over 5% Pd/C led to the
respective n-heptyl analog 4.
Several features of this work are worthy of note. (1)
The improved conditions for the cyclization of 11 to 12
have been applied successfully to the olivetol series and
promise to be general. (2) Cuprates derived from
resorcinol ethers are typically not very reactive and
require specialized conditions, viz., activation of apo-
verbenone with a Lewis acid and use of the higher-order
cuprate. The difficulty of separating the product of the
cuprate reaction from the auxiliary ligand on copper is
largely overcome by substituting imidazole for thiophene
in the cuprate. (3) The selective synthesis of either 14
or 15 is possible by choice of reaction conditions for the
homologation of 13.
F igu r e 2. Concentration diplacement curves for compounds
1-4: (a) displacement of specifically bound [3H]CP-55,940
from a CB1-enriched rat brain microsome preparation and (b)
displacement of specifically bound [3H]CP-55,940 from a CB2-
enriched mouse spleen preparation.
Ta ble 1. Ki Values for Compounds 1-4
Ki (nM) (95% confidence limits)
Recep tor Bin d in g Stu d ies
The abilities of 1-4 to displace radiolabeled CP-55,-
940 from purified rat forebrain synaptosomes and mouse
spleen synaptosomes were determined as described in
the methods. Figure 2 shows the displacement curves
for these four novel cannabinoids, and their calculated
Ki’s are shown in Table 1.
compd
brain
spleen
61.6
(44.4, 85.5)
9.5
(6.4, 14.2)
5.3
(3.9, 7.3)
14.3
1
2
3
4
5.8
(5.3, 6.4)
0.8
(0.6, 1.0)
1.2
(1.0, 1.4)
8.7
Exp er im en ta l Section
(7.8, 9.7)
47.6
(11.9, 17.1)
39.3
(-)-∆8-THC
1H- and 13C-NMR spectra were recorded at 300 MHz, 1H
(75 MHz, 13C), or 500 MHz, 1H (125 MHz, 13C), in either
deuteriochloroform (CDCl3) with chloroform (7.26 ppm, 1H;
77.00 ppm, 13C) or benzene-d6 with benzene (7.15 ppm, 1H;
128.0 ppm, 13C) as an internal reference. Chemical shifts are
given in δ; multiplicities are indicated as br (broadened), s
(singlet), t (triplet), q (quartet), m (multiplet); coupling con-
stants (J ) are reported in hertz (Hz). Infrared spectra were
recorded on a Perkin-Elmer IR 1430 spectrometer. Electron
impact mass spectra were performed on a VG-70SE mass
spectrometer. Mass spectral data are reported in the form of
m/ z (intensity relative to base ) 100). Thin-layer chroma-
tography (TLC) was performed on EM Reagents precoated
silica gel 60 F-254 analytical plates (0.25 mm). Flash column
chromatography was performed on Brinkmann silica gel
(0.040-0.063 mm). Tetrahydrofuran (THF) and diethyl ether
were distilled from sodium-benzophenone ketyl, N,N-dimeth-
ylformamide (DMF) and triethylamine (Et3N) from calcium
hydride, benzene from sodium, and dichloromethane (CH2Cl2)
from phosphorus pentoxide. Other reagents were obtained
commercially and used as received unless otherwise specified.
All reactions were performed under a static nitrogen or argon
atmosphere in flame-dried glassware. The purity and homo-
geneity of the products on which the high-resolution mass
spectral data are reported were determined on the basis of a
combination of chiral HPLC (Chiracel-OD, 2-propanol/hexane),
1
300 MHz H-NMR (94%), and multiple elution TLC analysis.
3,5-Dim eth oxya cetop h en on e (6). 3,5-Dimethoxybenzoic
acid (5) (3.0 g, 16.5 mmol) was dissolved in 100 mL of THF in
a 500 mL Morton flask and cooled to 0 °C. Methyllithium in
ether (50.7 mL, 66 mmol) was added in a fast stream with
vigorous stirring, and the solution was stirred at 0 °C for 2.5
h. Trimethylchlorosilane (43 mL, 344 mmol) was added
rapidly from an addition funnel with vigorous stirring. The
reaction mixture was allowed to warm to 25 °C during 40 min,
after which time dilute HCl (0.5 N, 140 mL) was added. The
reaction mixture was stirred for an additional 30 min. Ether
was added, and the organic phase was washed with saturated
NaHCO3 and brine. The aqueous phase was extracted twice
with ether, and the combined organic phase was dried over
MgSO4. Solvent evaporation followed by purification of the
residue by flash chromatography on silica gel eluting with 15-
18% ethyl acetate gradient in hexane gave 2.34 g (79% yield)
of methyl ketone 6: oil; IR (neat) 3090, 2970, 2840, 1680, 1600,

Unsaturated Side Chain Hydroxyhexahydrocannabinols
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3793
1
1360, 1260 cm-1; H-NMR (300 MHz, CDCl3) δ 7.04 (d, J )
cannula to a reaction flask containing predried p-toluene-
sulfonic acid (50 mg, 2 mol %), and the solution was cooled to
0 °C. Ethyl vinyl ether (3.7 mL, 67.1 mmol) was diluted with
3.7 mL of ether at 0 °C. The vinyl ether solution was dried
over molecular sieves (4 Å) for 15 min and then tranferred to
the resorcinol solution via cannula. The reaction mixture was
stirred at 0 °C for 5 h and then poured into vigorously stirring
saturated aqueous NaHCO3 at 0 °C. The aqueous phase was
extracted with 2 × 40 mL of ether. The combined organic
phase was washed with brine and dried over MgSO4. Solvent
evaporation followed by purification by flash column chroma-
tography, eluting with 7% ethyl acetate and 1% triethylamine
in hexane, gave 3.92 g (92% yield) of 9 as a mixture of
diastereoisomers (due to the stereogenic carbon of each of the
ethoxyethyl groups): IR (neat) 3080, 2930, 2230, 1585, 1380,
2.0 Hz, 2H), 6.61 (t, J ) 2.0 Hz, 1H), 3.79 (s, 6H), 2.53 (s, 3H).
(3,5-Dim eth oxyp h en yl)a cetylen e (7). A solution of n-
butyllithium in hexane (12.6 mL, 29.1 mmol) was added to a
solution of diisopropylamine (4.25 mL, 30.5 mmol) in 50 mL
of THF at 0 °C. The reaction mixture was stirred at 0 °C for
2 min and at -78 °C for 10 min. Ketone 5 (5.0 mL, 27.7 mmol)
was dissolved in 5 mL of THF and transferred to the reaction
mixture via cannula. Stirring was continued at -78 °C for
2.5 h, after which time diethyl chlorophosphate (4.40 mL, 30.5
mmol) was added dropwise. The reaction mixture was stirred
at -78 °C for 1 h and then slowly warmed to 25 °C during 1.5
h. A hexane solution of n-butyllithium (26.4 mL, 60.9 mmol)
was added to a solution of diisopropylamine (8.70 mL, 62.3
mmol) in 100 mL of THF at -78 °C. The enol phosphate
solution was cooled to -78 °C and added slowly to the solution
of base via cannula. The ensuing mixture was allowed to
warm to 25 °C during 5 h. The reaction was quenched with
water, and the reaction mixture was diluted with ether/hexane
(1:1). The organic phase was washed with 1 N HCl, the
aqueous phase was extracted twice with ether/hexane, and the
combined organic phases were washed with brine and dried
over MgSO4. Solvent evaporation followed by purification of
the residue by flash chromatography on silica gel, eluting with
10% ethyl acetate in hexane, gave 4.08 g (91% yield) of
acetylene 7: oil; IR (neat) 3290, 3090, 2105, 1590, 1450, 1420,
1250, 1210, 1175 cm-1 1H-NMR (300 MHz, C6D6) δ 7.12 (s,
;
2H), 6.93 (s, 1H), 5.14 (q, J ) 5.4 Hz, 2H), 3.58-3.53 (m, 2H),
3.27-3.22 (m, 2H), 2.21 (t, J ) 7.2 Hz, 2H), 1.44 (p, J ) 7.5
Hz, 2H), 1.28 (d, J ) 5.4 Hz, 6H), 1.23-1.14 (m, 4H), 1.00 (t,
J ) 7.2 Hz, 6H), 0.80 (t, J ) 7.2 Hz, 3H); MS m/ z 348 (M+,
0.2), 218 (67), 204 (72), 189 (42), 175 (59), 147 (45), 73 (100).
Exact mass calculated for C21H32O4, 348.2300; found, 348.2279.
Cu p r a te Ad d ition to Ap over ben on e. P r ep a r a tion of
10. Protected resorcinol 9 (1.05 g, 3.05 mmol) was dissolved
in 55 mL of THF and cooled to 0 °C. A solution of n-
butyllithium in hexane (2.4 mL, 3.66 mmol) was added very
slowly (over ca. 10 min), and the reaction mixture was stirred
at 0 °C for 1 h and at 25 °C for 1.5 h and subsequently cooled
to -78 °C. Imidazole (207 mg, 3.05 mmol) was dissolved in
28 mL of THF and cooled to -78 °C. A solution of n-
butyllithium in hexane (2.20 mL, 3.36 mmol) was added, and
stirring was continued at -78 °C for 1 h. The solution was
removed from the dry ice/acetone bath and allowed to warm
to 25 °C. Cuprous cyanide (327 mg, 3.65 mmol) was added in
small portions via an internal glass connection while the
reaction mixture was stirred vigorously at 25 °C. Stirring at
25 °C was continued for 5 min, after which time the reaction
mixture was cooled to -78 °C (green solution). The lithiated
resorcinol was added slowly to this solution via cannula. As
soon as the addition was complete, the reaction mixture was
cooled in an ice bath for 20 min (yellow solution) and then
cooled once again to -78 °C. Apoverbenone (331 mg, 2.44
mmol) was dissolved in 3 mL of THF. This solution was dried
over molecular sieves (4 Å) for 15 min and then cooled to -78
°C. Boron trifluoride etherate (0.30 mL, 2.44 mmol) was
added, the solution of Lewis acid-enone complex was trans-
ferred to the cuprate mixture via cannula, and stirring at -78
°C was continued for 2 h. The reaction was quenched with
concentrated NH4OH/saturated NH4Cl (1:9), and 50 mL of
ether was added. The aqueous phase was extracted with 2 ×
40 mL of ether. The combined organic phase was washed with
brine and dried over MgSO4. Solvent evaporation followed by
purification by flash column chromatography, eluting with a
gradient of 7-10% ethyl acetate in hexane, gave 728 mg of
crude cuprate adduct which was contaminated with ca. 20 mol
% of unreacted apoverbenone (pure product ca. 646 mg).
This mixture was dissolved in 10 mL of methanol, and
p-toluenesulfonic acid (32 mg, 4 mol %) was added. The
reaction mixture was stirred at 25 °C overnight. Most of the
methanol was removed in vacuo, and the concentrated solution
was diluted with ether and washed with saturated NaHCO3/
brine (1:1). The aqueous phase was extracted with 2 × 40 mL
of ether. The combined organic phase was washed with brine
and dried over MgSO4. Solvent evaporation followed by
purification by flash column chromatography, eluting with 20%
ethyl acetate in hexane, gave 461 mg of diol 11 (55% yield,
67% based on recovered 9): mp 167 °C; [R]D +54.7° (c ) 0.66,
CHCl3, 25 °C); IR (neat) 3350 (br), 2930, 2860, 2240, 1695,
1
1305, 1255 cm-1; H-NMR (300 MHz, CDCl3) δ 6.65 (d, J )
2.4 Hz, 2H), 6.47 (t, J ) 2.4 Hz, 1H), 3.78 (s, 6H), 3.04 (s, 1H);
13C-NMR (75 MHz, CDCl3) δ 160.4, 123.3, 110.2, 102.2, 83.6,
76.7, 55.3.
(3,5-Dim eth oxyp h en yl)-n -p en tyla cetylen e (8). Acety-
lene 7 (4.08 g, 25.2 mmol) was dissolved in 11 mL of THF and
cooled to 0 °C. A solution of methyllithium in ether (23.7 mL,
32.8 mmol) was added dropwise, and stirring was continued
for 15 min at 0 °C. To the solution was added n-pentyl bromide
(6.2 mL, 50.8 mmol) followed by 50 mL of DMSO. Stirring at
25 °C was continued overnight. The reaction was quenched
with water and the mixture diluted with ether. The organic
phase was washed with 4 × 25 mL of half-saturated brine and
dried over MgSO4. Solvent evaporation followed by purifica-
tion of the residue by flash chromatography on silica gel,
eluting with a gradient of 8-10% ethyl acetate in hexane, gave
4.13 g (72% yield) of alkyne 8: oil; IR (neat) 3080, 2920, 2225,
1590, 1420, 1250 cm-1; H-NMR (300 MHz, CDCl3) δ 6.56 (d,
1
J ) 2.4 Hz, 2H), 6.40 (t, J ) 2.4 Hz, 1H), 3.78 (s, 6H), 2.39 (t,
J ) 7.2 Hz, 2H), 1.63-1.57 (m, 2H), 1.45-1.34 (m, 4H), 0.92
(t, J ) 7.2 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 160.5, 125.4,
109.3, 100.9, 90.1, 80.6, 55.2, 31.2, 28.4, 22.3, 19.4, 14.0; MS
m/ z 232 (M+, 100), 203 (80), 189 (69), 177 (85), 151 (27). Exact
mass calculated for C15H20O2, 232.1463; found, 232.1448.
[3,5-Bis(2-eth oxyeth oxy)p h en yl]-n -p en tyla cetylen e (9).
Alkyne 8 (4.13 g, 17.8 mmol) was dissolved in 40 mL of CH2-
Cl2. 1-Methyl-1-cyclohexene (4.0 mL, 33.8 mmol) was added,
and the solution was cooled to -78 °C. Boron tribromide (1.0
M in CH2Cl2, 53.0 mL, 53.0 mmol) was diluted with 20 mL of
CH2Cl2, shaken with anhydrous K2CO3, cooled to -78 °C, and
added dropwise to the reaction mixture via cannula. The
temperature was slowly allowed to rise to 25 °C during 7 h.
The reaction mixture was poured into vigorously stirring
saturated aqueous NaHCO3 at 0 °C. Stirring was continued
overnight. The aqueous phase was extracted with 2 × 50 mL
of ether, and the combined organic phases were washed with
brine and dried over MgSO4. Solvent evaporation was followed
by filtration through silica gel eluting with 40% ethyl acetate
in hexane to give 3.31 g (91% yield) of the resorcinol: air-
sensitive oil; IR (neat) 3350 (br), 2930, 2860, 2240, 1590, 1450,
1255 cm-1; 1H-NMR (300 MHz, CDCl3) δ 6.65 (br s, 2H), 6.50
(d, J ) 2.1 Hz, 2H), 6.32 (J ) 2.1 Hz, 1H), 2.37 (t, J ) 6.9 Hz,
2H), 1.59 (p, J ) 7.2 Hz, 2H), 1.41-1.35 (m, 4H), 0.93 (t, J )
6.9 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 156.2, 125.8, 111.3,
103.0, 90.7, 80.1, 31.1, 28.4, 22.2, 19.3, 14.0; MS m/ z 204 (M+,
9), 147 (91), 86 (64), 84 (100). Exact mass calculated for
C13H16O2, 204.1150; found, 204.1154.
1610, 1590, 1450, 1255 cm-1 1H-NMR (300 MHz, CDCl3) δ
;
6.39 (s, 2H), 5.84 (br s, 2H), 3.96 (t, J ) 8.1 Hz, 1H), 3.45 (dd,
J ) 18.9, 7.6 Hz, 1H), 2.68-2.40 (m, 2H) 2.37-2.28 (m, 1H),
2.35 (t, J ) 7.2 Hz, 2H), 1.56 (p, J ) 7.2 Hz, 2H), 1.42-1.25
(m, 6H), 1.35 (s, 3H), 0.99 (s, 3H), 0.90 (t, J ) 7.1 Hz, 3H);
13C-NMR (75 MHz, CDCl3) δ 219.2, 155.3 (2C), 122.6 (2C),
116.8, 111.6, 90.1, 79.9, 58.0, 46.7, 42.3, 37.6, 31.1, 29.6, 28.4,
26.1, 24.5, 22.2 (2C), 19.3, 14.0; MS m/ z 340 (M+, 84), 338
The material from the preceding step was quickly protected
as the bis(ethoxyethyl) ether. The resorcinol (2.50 g, 12.2
mmol) was dissolved in 40 mL of ether and transferred via

3794 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Busch-Petersen et al.
(58), 297 (59), 257 (100), 241 (66), 217 (88). Exact mass
calculated for C22H28O3, 340.2065; found, 340.2038.
of ethanol. The heterogeneous mixture was stirred at 25 °C
for 4 h; then the reaction was quenched with saturated
aqueous NaH2PO4 and the mixture diluted with ether. The
aqueous phase was extracted with 4 × 20 mL of ether; the
combined organic extracts were dried (MgSO4), evaporated,
and purified by flash column chromatography, eluting with
5% ethyl acetate in hexane, to produce 94 mg (85% overall
yield) of 15: oil; [R]D -82.2° (c ) 0.59, EtOH, 25 °C); IR (neat)
3060, 2920, 2850, 2710, 2230, 1725, 1600, 1550, 1460, 1405,
Cycliza tion of th e Dih yd r oben zop yr a n Rin g. Syn th e-
sis of 12. Resorcinol 11 (164 mg, 0.48 mmol) was dissolved
in 27 mL of dry nitromethane, and the solution was cooled to
5 °C. Trimethylsilyl triflate (0.29 M in nitromethane, 0.60 mL,
34 mol %) was added dropwise. Stirring was continued for
1.5 h while the temperature was allowed to rise to 25 °C. The
reaction was quenched with saturated aqueous NaHCO3/brine
(1:1), and 60 mL of ether was added. The aqueous phase was
extracted with 2 × 40 mL of ether, and the combined organic
phase was washed with brine and dried over MgSO4. Solvent
evaporation followed by filtration through silica gel, eluting
with 25% ethyl acetate in hexane, gave 146 mg (89% yield) of
12: oil; [R]D -54.4° (c ) 0.16, CHCl3, 25 °C); IR (neat) 3230
(br), 2930, 2860, 2230, 1695, 16.15, 1570, 1415, 1360, 1100
1
1355, 1350, 1250, 1135, 1060, 835 cm-1; H-NMR (300 MHz,
CDCl3) δ 9.62 (s, 1H), 6.50 (d, J ) 1.2 Hz, 1H), 6.38 (d, J ) 1.2
Hz, 1H), 3.42 (br d, J ) 12.3 Hz, 1H), 2.44-2.33 (m, 1H), 2.40
(td, J ) 10.8, 2.4 Hz, 1H), 2.35 (t, J ) 6.9 Hz, 2H), 2.10 (br d,
J ) 12.9 Hz, 1H), 1.98 (br d, J ) 12.9 Hz, 1H), 1.63-1.11 (m,
9H), 1.36 (s, 3H), 1.03 (s, 3H), 0.99 (s, 9H), 0.91 (t, J ) 6.9 Hz,
3H), 0.90 (m, 1H), 0.28 (s, 3H), 0.16 (s, 3H); 13C-NMR (75 MHz,
CDCl3) δ 203.3, 154.7 (2C), 154.7, 122.9, 116.1, 114.3, 114.2,
89.7, 80.3, 76.6, 50.5, 49.0, 35.6, 31.1, 30.2, 28.4, 27.4, 26.9,
25.9, 25.8 (3C), 22.2, 19.3, 18.6, 18.2, 14.0, -3.7, -4.3; MS m/ z
468 (M+, 38), 411 (48), 167 (36), 149 (100), 73 (31). Exact mass
calculated for C29H44O3Si, 468.3059; found, 468.3071.
cm-1 1H-NMR (300 MHz, CDCl3) δ 7.29 (br s, 1H), 6.46 (s,
;
1H), 6.44 (s, 1H), 4.03 (dt, J ) 14.7, 1.8 Hz, 1H), 2.87 (td, J )
11.1, 3.6 Hz, 1H), 2.62 (br d, J ) 15.6 Hz, 1H), 2.54-2.42 (m,
2H), 2.35 (t, J ) 6.9 Hz, 2H), 2.18-2.12 (m, 1H), 2.10 (q, J )
14.7 Hz, 1H), 1.94 (td, J ) 11.7, 2.7 Hz, 1H), 1.60-1.25 (m,
6H), 1.46 (s, 3H), 1.09 (s, 3H), 0.91 (t, J ) 6.9 Hz, 3H); 13C-
NMR (75 MHz, CDCl3) δ 215.6, 155.5, 154.7, 123.5, 112.8,
111.0, 110.3, 89.9, 80.1, 76.8, 47.7, 44.2, 40.6, 34.9, 31.1, 28.4,
27.6, 26.9, 22.2, 19.3, 18.7, 14.0; MS m/ z 340 (M+, 100), 325
(36), 297 (24), 257 (88), 217 (23), 175 (20). Exact mass
calculated for C22H28O3, 340.2065; found, 340.2041.
Diol 1. Aldehyde 15 (45 mg, 0.124 mmol) was dissolved in
1.5 mL of EtOH and cooled to 0 °C. A solution of 11 mg (0.289
mmol) of NaBH4 dissolved in 0.5 mL of EtOH was added via
cannula. The reaction mixture was stirred at 0 °C for 30 min,
the reaction quenched with water, and the mixture diluted
with ether. The aqueous phase was extracted twice with ether,
and the combined organic extract was washed with brine and
dried (MgSO4). The solvent was evaporated, and the crude
product was dissolved in 3 mL of THF and cooled to 0 °C.
Tetrabutylammonium fluoride (48 mg, 0.188 mmol) in 0.7 mL
of THF was added, the mixture was stirred at 0 °C for 45 min,
and then the reaction was quenched with water. Ether was
added (5 mL), and the aqueous phase was extracted with 2 ×
10 mL of ether. The combined organic extract was washed
with brine, dried (MgSO4), evaporated, and purified by flash
chromatography (35% ethyl acetate in hexane) to produce 34
mg of 1 (95% overall yield): oil; [R]D -110.9° (c ) 1.02, EtOH,
25 °C); IR (neat) 3320 (br), 2920, 2850, 2230, 1610, 1455, 1410,
Silyl Eth er 13. Ketophenol 12 (146 mg, 0.43 mmol) was
dissolved in DMF containing tert-butyldimethylsilyl chloride
(1.05 mL of a 1.11 M in DMF, 0.96 mmol) at 25 °C. Imidazole
(100 mg, 1.45 mmol) was added to the solution after the
starting material had dissolved. The reaction mixture was
stirred at 25 °C overnight, and the reaction was subsequently
quenched with water. Addition of 40 mL of ether/hexane (1:
1) was followed by extraction of the aqueous phase with 2 ×
25 mL of hexane. The combined organic phase was washed
with brine and dried over MgSO4. Solvent evaporation was
followed by purification by filtration through silica gel, eluting
with 10% ethyl acetate in hexane, to produce 180 mg (92%
yield) of the silyl ether 13: oil; [R]D -45.7° (c ) 1.68, EtOH,
25 °C); IR (neat) 2970, 2920, 2850, 2220, 1705, 1600, 1545,
1460, 1400, 1355, 1250, 830 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 6.53 (d, J ) 1.2 Hz, 1H), 6.38 (d, J ) 1.2 Hz, 1H), 3.72 (dt,
J ) 14.7, 1.8 Hz, 1H), 2.71 (td, J ) 11.8, 3.3 Hz, 1H), 2.55 (br
d, J ) 15.6 Hz, 1H), 2.45-2.35 (m, 2H), 2.35 (t, J ) 6.9 Hz,
2H), 2.16-2.09 (m, 1H), 2.06 (q, J ) 14.7 Hz, 1H), 1.93 (td, J
) 11.7, 2.7 Hz, 1H), 1.60-1.25 (m, 6H) 1.45 (s, 3H), 1.06 (s,
3H), 1.00 (s, 9H), 0.91 (t, J ) 6.9 Hz, 3H), 0.26 (s, 3H), 0.17 (s,
3H); 13C-NMR (75 MHz, CDCl3) δ 209.9, 154.5, 154,4, 123.3,
115,4, 114.4, 114.2, 90.0, 80.1, 76.7, 47.8, 45.5, 40.7, 35.2, 31.1,
28.4, 27.6, 26.7, 25.9 (3C), 22.2, 19.3, 18.5, 18.2, 14.0, -3.3,
-3.7; MS m/ z 454 (M+, 36), 397 (100), 341 (10), 315 (8), 287
(7). Exact mass calculated for C28H42O3Si, 454.2871; found,
454.2905.
1
1260, 1035 cm-1; H-NMR (300 MHz, CDCl3) δ 6.45 (d, J )
1.4 Hz, 1H), 6.30 (d, J ) 1.4 Hz, 1H), 6.00 (br s, 1H), 3.55 (dd,
J ) 10.6, 5.9 Hz, 1H), 3.48 (dd, J ) 10.6, 5.9 Hz, 1H), 3.25 (br
d, J ) 12.5 Hz, 1H), 2.45 (td, J ) 11.3, 2.6 Hz, 1H), 2.34 (t, J
) 6.9 Hz, 2H), 1.91-1.88 (m, 2H), 1.79-1.75 (m, 1H), 1.56 (p,
J ) 7.0 Hz, 2H), 1.46 (td, J ) 11.8, 1.7 Hz, 1H), 1.43-1.29 (m,
4H), 1.35 (s, 3H), 1.11 (m, 2H), 1.03 (s, 3H), 0.91 (t, J ) 7.2
Hz, 3H), 0.75 (q, J ) 11.8 Hz, 1H); 13C-NMR (75 MHz, CDCl3)
δ 154.9, 154.9, 122.7, 113.5, 113.2, 110.3, 89.7, 80.2, 77.1, 68.5,
49.3, 40.4, 35.1, 33.0, 31.0, 29.6, 28.4, 27.6, 27.4, 22.2, 19.3,
18.9, 14.0; MS m/ z 356 (M+, 100), 313 (46), 217 (95), 149 (33),
121 (23), 95 (34). Exact mass calculated for C23H32O3, 356.2351;
found, 356.2337.
(Z)-Alk en e 2. Acetylenic diol 1 (111 mg, 0.312 mmol) was
dissolved in 3.5 mL of benzene. Lindlar catalyst (2.5% on
CaCO3, 53 mg, 4 mol %) was suspended in 1.45 mL of a 0.03
M solution of quinoline in benzene under ca. 1 atm of hydrogen.
The solution of 1 was added via cannula, and the reaction
mixture was stirred for 2.5 h. The catalyst was removed by
filtration through Celite and washed with ether, and the
solvent was evaporated to give the crude product. Purification
was effected by HPLC (Whatman Partisil 10 M9/50, normal
phase, 35% ethyl acetate in hexane) to produce alkene 2 in
65% yield: oil; [R]D -84.6° (c ) 0.74, EtOH, 25 °C); IR (neat)
3350 (br), 2920, 2850, 1615, 1565, 1425, 1400, 1260, 1130,
1040, 850 cm-1; 1H-NMR (500 MHz, C6D6) δ 6.85 (s, 1H), 6.39
(d, J ) 11.8 Hz, 1H), 6.08 (s, 1H), 5.59 (dt, J ) 11.8, 7.1 Hz,
1H), 5.34 (br s, 1H), 3.48 (br d, J ) 12.8 Hz, 1H), 3.25 (dd, J
)10.4, 5.6 Hz, 1H), 3.23 (dd, J ) 10.4, 6.5 Hz, 1H), 2.53 (td, J
) 10.9, 2.4 Hz, 1H), 2.38 (qd, J ) 7.5, 1.4 Hz, 2H), 1.65-1.63
(m, 1H), 1.58-1.54 (m, 2H), 1.42 (td, J ) 10.8, 1.9 Hz, 1H),
1.33 (p, J ) 7.5 Hz, 2H), 1.28 (s, 3H), 1.20-1.14 (m, 4H), 0.98
(s, 3H), 0.84-0.78 (m, 2H), 0.83 (t, J ) 7.1 Hz, 3H), 0.71 (q, J
) 11.8 Hz, 1H); 13C-NMR (125 MHz, C6D6) δ 156.0, 155.7,
137.7, 133.1, 129.1, 112.2, 111.0, 108.9, 76.8, 68.6, 49.7, 40.7,
35.6, 33.7, 31.8, 30.1, 29.7, 29.3, 27.8, 27.7, 22.9, 19.1, 14.2;
Aldeh yde 15. (Methoxymethyl)triphenylphosphonium chlo-
ride (247 mg, 0.72 mmol) was suspended in 6 mL of dry
benzene. Sodium tert-amylate (1.24 M in benzene, 0.58 mL,
0.72 mmol), from NaH and tert-amyl alcohol, was added, and
the reaction mixture was stirred for 5 min at 25 °C. Protected
ketone 12 (107 mg, 0.24 mmol) was dissolved in the minimum
amount of benzene and transferred to the solution of the ylide
via cannula. The reaction mixture was stirred at 70 °C for
1.5 h. Quenching with saturated aqueous NH4Cl, dilution with
ether, and extraction (3 × 10 mL) with ether produced an
organic phase which was washed with brine, dried (MgSO4),
and evaporated. The residue was dissolved in 16 mL of
dichloromethane, 155 mg (ca. 0.9 mmol) of wet trichloroacetic
acid was added, and the mixture was stirred at 25 °C for 30
min. The reaction was quenched with saturated aqueous
NaHCO3/brine (1:1), and the mixture was diluted with dichlo-
romethane. The aqueous phase was extracted with 3 × 20
mL of dichloromethane, and the combined organic extract was
washed with brine, dried (MgSO4), and evaporated. The
residue which consisted of a mixture of aldehydes 14 and 15
was dissolved in 10 mL of ethanol and added to 71 mg (0.54
mmol) of powdered potassium carbonate suspended in 10 mL

Unsaturated Side Chain Hydroxyhexahydrocannabinols
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3795
MS m/ z 358 (M+, 100), 315 (45), 297 (17), 219 (64), 175 (16).
Exact mass calculated for C23H34O3, 358.2508; found, 358.2500.
(E)-Alk en e 3. Crude (Z)-alkene 2 from the semihydroge-
nation of 1 (86 mg, 0.168 mmol, ca. 70% Z) was dissolved in
4.3 mL of benzene containing thiophenol (0.02 M) and ACN
(0.006 M). The reaction mixture was heated to reflux for 4 h.
After cooling to 25 °C, the reaction mixture was diluted with
ether and washed twice with brine. The aqueous phase was
extracted with 3 × 10 mL of ether; the combined organic
extracts were dried (MgSO4) and evaporated. Filtration of the
residue through silica gel (50% ethyl acetate in hexane)
followed by purification by HPLC (Whatman Partisil 10 M9/
50 normal phase, 35% ethyl acetate in hexane) produced 44
mg (74% yield) of 3: oil; [R]D -54.4° (c ) 0.24, EtOH, 25 °C);
IR (neat) 3350 (br), 2920, 2850, 1660, 1630, 1600, 1460, 1410,
for single-bond rotations and 10° for two-bond rotations. Each
sampled conformer was minimized with
a
two-step
minimization: steepest descent method for the first 100
iterations and then conjugate gradient method until the
maximum derivative was less than 0.001 kcal mol-1 Å-1
.
Discu ssion
A review of the existing literature reveals that the
cannabinoid side chain plays a major role in determin-
ing the drug’s potency, indicative of a hydrophobic
pocket in the receptor. Although a considerable number
of structure-activity correlations have dealt with the
cannabinoid side chain, most of these have focused on
chain length, its branching, or the introduction of
heteroatoms,1,2,20 and little attention has been given to
stereochemical considerations. This present contribu-
tion has sought to restrict rotation around the C1′-C2′
bond through the introduction of double or triple bonds
to obtain two 1′-alkenes (cis and trans) and the corre-
sponding 1′-alkyne side chain analogs. The flexible
n-heptyl analog was synthesized and used as the
prototype in our comparisons. Our design has also
incorporated in the above group of analogs pharma-
cophoric features that are expected to lead to optimal
interaction with the cannabinoid receptor (CB1). These
include a seven-carbon side chain and a 9â-hydroxym-
ethyl group as the northern aliphatic hydroxyl phar-
macaphore.
Our study was also extended to include the newly
discovered cannabinoid receptor subtype CB2. The
affinity of all four analogs for the two receptors was
obtained by a displacement binding assay using the
standard cannabinoid radioligand [3H]CP-55,940 and
suitable membrane preparations known to contain CB1
and CB2 receptors. While the rat brain has been shown
to be a reliable source for CB1, there is still no standard
CB2 preparation. Recent work has utilized membranes
from cell lines transfected with the CB2 receptors.21 In
our laboratory we have found the mouse spleen to be
an excellent source of CB2,22 a finding congruent with
an earlier report by Kaminski et al.23
1
1380, 1260, 1090, 1000, 820 cm-1; H-NMR (500 MHz, C6D6)
δ 6.84 (s, 1H), 6.29 (d, J ) 15.6 Hz, 1H), 6.13 (dt, J ) 15.6, 7.1
Hz, 1H), 5.88 (s, 1H), 4.22 (br s, 1H), 3.34 (br d, J ) 12.8 Hz,
1H), 3.27 (dd, J ) 10.4, 6.1 Hz, 1H), 3.23 (dd, J ) 10.4, 6.6
Hz, 1H), 2.53 (td, J ) 10.9, 2.4 Hz, 1H), 2.38 (q, J ) 6.6 Hz,
2H), 1.73-1.70 (m, 1H), 1.57-1.52 (m, 2H), 1.42 (td, J ) 10.3,
2.4 Hz, 1H), 1.37-1.24 (m, 6H), 1.28 (s, 3H), 0.97 (s, 3H), 0.90-
0.77 (m, 2H), 0.87 (t, J ) 7.1 Hz, 3H), 0.70 (q, J ) 11.8 Hz,
1H); 13C-NMR (75 MHz, CDCl3) δ 156.0, 155.7, 137.9, 130.6,
130.2, 112.0, 108.6, 105.3, 76.7, 68.4, 49.6, 40.8, 35.7, 33.6, 31.7,
30.2, 29.9, 29.5, 27.8, 27.6, 22.9, 19.1, 14.2; MS m/ z 358 (M+,
100), 315 (28), 297 (12), 271 (20), 219 (71). Exact mass
calculated for C23H34O3, 358.2508; found, 358.2503.
Alk a n e 4. A mixture of acetylenic diol 1 (7.8 mg, 0.022
mmol) and 10% palladium on carbon in 0.4 mL of absolute
ethanol was stirred at room temperature under 1 atm of
hydrogen for 5 h. The catalyst was removed by filtration
through Celite using diethyl ether as solvent. The solvents
were then removed, and the residue was chromatographed on
silica gel using 30% diethyl ether-petroleum ether as eluent
to afford 6.5 mg (82%) of 4: oil; IR (neat) 3350 (br), 2920, 2850,
1620, 1575, 1450, 1135, 1040 cm-1; 1H-NMR (300 MHz, C6D6)
δ 6.64 (d, J ) 0.9 Hz, 1H), 5.79 (d, J ) 0.9 Hz, 1H), 4.90 (br s,
1H), 3.45 (br d, J ) 12.0 Hz, 1H), 3.25 (d, J ) 6.0 Hz, 2H),
2.51 (td, J ) 11.1, 2.4 Hz, 1H), 2.45 (t, J ) 7.8 Hz, 2H), 1.69-
1.63 (m, 1H), 1.59-1.52 (m, 2H), 1.42 (td, J ) 10.3, 2.4 Hz,
1H), 1.37-1.22 (m, 10H), 1.28 (s, 3H), 0.99 (s, 3H), 0.90-0.77
(m, 2H), 0.87 (t, J ) 7.1 Hz, 3H), 0.71 (q, J ) 12.0 Hz, 1H);
MS m/ z 360 (M+, 100), 358 (35), 317 (63), 276 (90), 221 (82).
Exact mass calculated for C23H36O3, 360.2664; found, 360.2635.
P h a r m a cologica l Meth od s. Rat forebrain synaptosomal
membranes were prepared by the method of Dodd et al.17 and
were used to assess the affinity of 1-4 for the CB1 binding
sites. Mouse spleen membranes were used as the source
material for CB2 receptors. The displacement of specifically
bound tritiated CP-55,940 from these membranes using a
standard filtration assay was used to determine the IC50 for
the test compounds. Briefly, 40 µg of protein was incubated
for 1 h at 30 °C in the presence of 0.76 nM [3H]CP-55,940 and
various concentrations of test compound, final volume 200 µL.
Nonspecific binding was defined by 100 nM cold CP-55,940.
The incubation was terminated by rapid filtration and wash-
ing, and the amount of specifically bound [3H]CP-55,940 was
determined. Data normalized between 0 and 100% specific
binding were plotted against log concentration of test com-
pound, and IC50 values were determined from the average of
at least three experiments run in duplicate, by fitting to a four-
variable nonparametric equation, holding the maximum to 100
and the minimum to 0. IC50 values were converted to Ki values
according to the method of Cheng and Prusoff.18
Our results indicate that all the side chain analogs
reported here have relatively high affinities for both
CB1 and CB2, thus supporting earlier SAR1,2 according
to which seven carbon chains in cannabinoids are
associated with high potencies and affinities. Although
this observation appears to be true for both CB1 and
CB2, the affinities for the CB2 were invariably some-
what lower. This observation may suggest different side
chain SAR criteria for CB2, especially with regard to
side chain length and branching.
The data clearly indicate that the cis-alkene analog
2 had the highest affinity for CB1 followed by the trans-
alkene 3. The parent n-heptyl had the lowest affinity,
while the l′-alkyne analog was intermediate.
Our results also suggest differences between CB1 and
CB2 with regard to classical cannabinoid side chain
SAR. Of all the analogs, 2 showed the widest separation
in affinities for CB1 and CB2, while the more flexible
n-heptyl analog 4 showed the smallest separation. It
is difficult at this time to fully explain these results in
terms of ligand-receptor interactions. This task is
rendered difficult by the fact that all analogs discussed
here still possess a large degree of flexibility. Neverthe-
less, the stereochemical differences between analogs
with respect to their abilities for optimal interactions
Molecu la r Mod elin g. Molecular modeling was carried out
with the Tripos SYBYL molecular modeling package on an
Indigo2 SGI workstation. A molecular model of ∆9-THC was
initially generated from the X-ray crystallographic data of ∆9-
tetrahydrocannabinolic acid19 and energy-minimized using the
Tripos program. The minimum energy conformation of ∆9-
THC was then used as a starting template, and the structures
of 1-4 were generated by deletion and/or addition of atoms
at standard bond lengths and bond angles. Dihedral drives
were used to probe the rotational space of the side chain and
calculate rotational energy barriers. Intervals of 5° were used

3796 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Busch-Petersen et al.
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F igu r e 3. Rotation around the C1′-C2′ bond restricted in the
three cannabinoids (1-3). As a result these analogs experience
different conformational spaces upon rotation around the Ar-
C1′ bond.
with the CB receptor sites of action are more visible if
we explore the differences in available conformational
space for the analogs in question. An exploration of the
conformational space is shown in Figure 3.
It is interesting to note that the side chain in 2 is
expected to orient in a manner similar with the dim-
ethylheptyl analogs24 running perpendicular to the long
axis of the tricyclic system and being in closest proxim-
ity with the phenolic ring when compared with the other
analogs. Conversely the alkyne analog would orient
furthest from the phenolic ring. There is also an
interesting similarity between the pharmacophorically
optimal cis-hept-l′-ene chain and that of the last seven
carbons of the arachidonic acid portion of the putative
native ligand anandamide.
The results presented here are encouraging and lead
us to the prediction that stereochemically defined side
chain analogs of classical cannabinoids can define the
requirements for interaction with CB receptor sites and
open the door for compounds which are selective be-
tween CB1 and CB2. These goals are currently being
pursued through design and synthesis of other more
conformationally restricted side chain cannabinoids.
Ack n ow led gm en t. Acknowledgement is made to
NIDA (DA07215) for their generous support of this
work.
Refer en ces
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