1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New high affinity ligands for the cannabinoid CB1 and CB2 receptors

Article abstract of DOI:10.1016/j.bmcl.2006.07.051

Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB₁ and CB₂ receptors were determined. In the 2-phenyl series (5) the N-alkyl group was varied from n-propyl to n-heptyl. A second series of 23 1-pentyl-2-aryl-4-(1-naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB₁ receptor affinities in the 6-30 nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R = C₅H₁₁) support the hypothesis that these pyrroles interact with the CB₁ receptor primarily by aromatic stacking.

Full text of DOI:10.1016/j.bmcl.2006.07.051

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5432–5435
1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New high affinity ligands
for the cannabinoid CB1 and CB2 receptors
John W. Huffman,a,* Lea W. Padgett,a Matthew L. Isherwood,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 12 June 2006; revised 17 July 2006; accepted 18 July 2006
Available online 4 August 2006
Abstract—Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB1 and
CB2 receptors were determined. In the 2-phenyl series (5) the N-alkyl group was varied from n-propyl to n-heptyl. A second series
of 23 1-pentyl-2-aryl-4-(1-naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB1 receptor affinities
in the 6–30 nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R = C5H11) support the hypothesis that
these pyrroles interact with the CB1 receptor primarily by aromatic stacking.
Ó 2006 Elsevier Ltd. All rights reserved.
Several years ago we reported the synthesis, CB1 recep-
tor affinities, and in vivo pharmacology for a series of
1-alkyl-3-(1-naphthoyl)pyrroles (1, R = C3H7 to C7H15).1
The 1-propyl, 1-butyl and 1-heptyl analogs have little
affinity for the CB1 receptor, however, the 1-pentyl com-
pound (JWH-030, 1, R = C5H11) has moderate affinity
for the CB1 receptor with Ki = 87 3 nM and is quite
potent in vivo in the spontaneous activity and tail flick
procedures. It is considerably less potent in the rectal
temperature and ring immobility protocols. The 1-hexyl-
pyrrole derivative (JWH-031, 1, R = C6H13) has little
affinity for the CB1 receptor (Ki = 399 109 nM), but
has moderate potency in the spontaneous activity and
tail flick assays. Subsequently JWH-030 was found to
inhibit the electrically stimulated contractions of the iso-
lated mouse vas deferens.2
O
O
N
H C
3
N
R
O
N
O
2
1
CH
3
O
OH
H C
3
N
R
H C
3
O
CH
3
H C
3
The design of these cannabimimetic pyrroles was based
upon a model for a general pharmacophore that related
the structures of the Sterling Winthrop aminoalkylin-
doles, in particular WIN-55,212-2 (2), with those of tra-
ditional cannabinoids such as D9-tetrahydrocannabinol
(D9-THC, 3).3 In this model the phenolic hydroxyl of
THC was assumed to align with the ketonic carbonyl
3
4
of WIN-55,212-2 and the cyclohexene ring of THC
was overlaid upon the naphthalene portion of the amino-
alkylindole. In this alignment the aminoalkyl portion of
WIN-55,212-2 corresponded to the alkyl side chain of
THC. This suggested that the aminoalkyl portion
of 2 could be replaced by a simple alkyl group and a
series of 1-alkyl-2-methyl-3-(1-naphthoyl)indoles (4)
Keywords: Cannabinoid; Cannabimimetic pyrroles; CB1 receptor; CB2
receptor.
*
Corresponding author. E-mail: huffman@clemson.edu
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.07.051

J. W. Huffman et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5432–5435
5433
wasprepared;theiraffinitiesfortheCB1 receptorandinvi-
vopharmacologyweredetermined. Several oftheseindole
derivatives have high affinity (Ki = 10–48 nM) for the CB1
receptor and are quite potent in vivo.3,4 2-Methyl-1-pen-
tyl-3-(1-naphthoyl)indole (JWH-007, 4, R = C5H11) has
the highest affinity for the CB1 receptor of this series of in-
dole derivatives (Ki = 10 4 nM) and is quite potent in
the mouse model of cannabinoid activity.
and 1-heptyl-2-phenyl-4-(1-naphthoyl)pyrrole (JWH-
146, 5, R = C7H15) upon treatment with sodium hydride
and the appropriate alkyl bromide.9
Due to inconsistent results and poor yields in the synthe-
sis of 2-phenylpyrrole, an alternative synthetic approach
to indoles 5 was developed (Scheme 1). Bromination of
1-propyl- (1, R = C3H7) or 1-butyl-3-(1-naphthoyl)pyr-
role (1, R = C4H9) with NBS, or better 1,3-dibromo-
5,5-dimethylhydantoin,10 provided the corresponding
2-bromopyrrole derivatives (7, R = C3H7 and C4H9),
which were used in the subsequent step without further
purification. Suzuki coupling11 with phenylboronic acid
under standard conditions using (Ph3P)4Pd and
Na2CO3, in a mixture of toluene, ethanol, and water,
provided 1-propyl- (JWH-156, 5, R = C3H7) and
1-butyl-2-phenyl-4-(1-naphthoyl)pyrrole (JWH-150, 5,
R = C4H9) in 59% and 52% yield, respectively.
Although the high CB1 receptor affinity and in vivo
potency of 4 (R = C5H11) and related indoles supported
the alignment that led to the development of these can-
nabimimetic indoles,3,4 subsequent studies indicate that
these compounds interact with the CB1 receptor primar-
ily by aromatic stacking.5–7 These observations suggest
that the addition of an aryl substituent to cannabimimet-
ic pyrroles similar to JWH-030 (1, R = C5H11) would
lead to compounds with enhanced affinity for the CB1
receptor. In order to test this hypothesis, we have pre-
pared two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyr-
The affinities of pyrroles 5 for the CB1 receptor were
determined by measuring their ability to displace
[3H]CP-55,940 from its binding site in a membrane prep-
aration from rat brain,12 and CB2 receptor affinities
were determined by measuring the ability of the com-
pounds to displace [3H]CP-55,940 from a cloned human
receptor preparation.13 The results of these determina-
tions are summarized in Table 1. Also included in Table
1 are the receptor affinities for WIN-55,212-2 (1) and D9-
THC (3).
roles. Initially
a
series of 1-alkyl-2-phenyl-4-(1-
naphthoyl)pyrroles (5, R = C3H7 to C7H15) was pre-
pared. Following the observation that four of these com-
pounds have from moderate to high affinity for the CB1
receptor, the effect upon receptor affinity of varying the
C-2 aryl substituent while maintaining a 1-pentyl group
was investigated (6, Ar = various aromatic groups).
O
O
Based upon the high CB1 and CB2 receptor affinities of
1-pentyl- (JWH-145, 5, R = C5H11) and 1-hexyl-2-phen-
yl-4-(1-naphthoyl)pyrrole (JWH-147, 5, R = C6H13) a
second series of 2-aryl-4-(1-naphthoyl)pyrroles was syn-
Ar
C H
6
5
N
N
R
C H
5
11
Table 1. Receptor affinities (mean SEM) of 1-alkyl-2-phenyl-4-(1-
naphthoyl)pyrroles (5), WIN-55,212-2 (2), and D9-THC (3)
5
6
The initial synthesis of 2-phenylpyrroles 5 was based
upon that used for the preparation of pyrroles 1.1 2-Phe-
nylpyrrole was prepared in poor (22%) yield from ace-
tophenone oxime and 1,2-dichloroethane by the
procedure of Korostova et al.8 and was converted to
the 1-p-toluenesulfonyl derivative with p-toluenesulfonyl
chloride in the presence of sodium hydride. Friedel–
Crafts acylation with 1-naphthoyl chloride in the pres-
ence of aluminum chloride provided 2-phenyl-1-p-tolu-
enesulfonyl-4-(1-naphthoyl)pyrrole (5, R = C7H7SO2).
Basic hydrolysis gave 2-phenyl-4-(1-naphthoyl)pyrrole
(5, R = H), which was converted to 1-pentyl- (JWH-
145, 5, R = C5H11), 1-hexyl- (JWH-147, 5, R = C6H13),
Ki (nM)
CB1
CB2
WIN-55,212-2 (2)
D9-THC (3)
1.9 0.1a
41 2b
0.28 0.16a
36 10a
1-Alkyl Group, R
Propyl, JWH-156
Butyl, JWH-150
Pentyl, JWH-145
Hexyl, JWH-147
Heptyl, JWH-146
404 18
104 18
15
60
14
11
21
1
2
1
2
2
6.4 0.4
7.1 0.2
62
5
a Ref. 13.
b Ref. 12.
O
a
b or c
5 or 6
1
Br
N
R
7
Scheme 1. Reagents and conditions: (a) NBS, or 1,3-dibromo-5,5-dimethylhydantoin, THF, À78 °C; (b) (Ph3P)4Pd, Na2CO3, C6H5CH3, C2H5OH,
H2O, reflux; (c) Pd(OAc)2, (o-CH3C6H4)3P, K2CO3, (C4H9)4NBr, C6H5CH3, H2O, reflux.

5434
J. W. Huffman et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5432–5435
Table 2. Receptor affinities (mean SEM) of 1-pentyl-2-aryl-4-(1-
naphthoyl)pyrroles (6)
thesized in order to obtain data regarding the structure–
activity relationships of this class of cannabinoids at
both receptors. For this series of compounds an N-pentyl
substituent was employed and the aryl group was varied.
The pentyl group was selected since JWH-030 (1,
R = C5H11) has the highest CB1 receptor affinity in the
original series of cannabimimetic pyrroles and JWH-
145 (5, R = C5H11) has high affinity for both receptors.
Aryl group, Ar
Ki (nM)
CB2
CB1
14
Phenyl, JWH-145
2
6.4 0.4
ortho-isomers
o-Methylphenyl, JWH-370
o-Ethylphenyl, JWH-365
o-Butylphenyl, JWH-373
o-Methoxyphenyl, JWH-292
o-Fluorophenyl, JWH-307
o-Chlorophenyl, JWH-369
o-Trifluoromethylphenyl, JWH-372
5.6 0.4
4.0 0.5
3.4 0.2
17
60
29
1
3
1
69
20
2
1
The original synthetic design for pyrroles 6 was based
upon the route initially employed for the synthesis of
the 2-phenylpyrroles (5), but was to employ an efficient
alternative synthesis of 1-p-toluenesulfonyl-2-arylpyr-
roles.14 However, with the exception of 1-p-toluene-
sulfonyl-2-phenylpyrrole (5, R = C7H7SO2), Friedel–
Crafts reaction of other 1-p-toluenesulfonyl-2-aryl-
pyrroles with 1-naphthoyl chloride under a variety of
conditions afforded either complex mixtures of regioi-
somers or the undesired 2-aryl-5-(1-naphthoyl) com-
pound.15 Pyrroles 6 were successfully synthesized by a
modification of the procedure outlined in Scheme 1
using JWH-030 (1, R = C5H11) as the starting material.
Bromination with 1,3-dibromo-5,5-dimethylhydantoin
gave 1-pentyl-2-bromo-4-(1-naphthoyl)pyrrole (7, R =
C5H11) plus a small amount of the 3-bromo-4-(1-naph-
thoyl) isomer, from which 7, R = C5H11 was isolated
in 70% yield.
7.7 1.8
7.9 0.4
3.3 0.2
5.2 0.3
8.2 0.2
77
2
meta-isomers
m-Methylphenyl, JWH-346
m-Methoxyphenyl, JWH-367
m-Fluorophenyl, JWH-368
m-Chlorophenyl, JWH-246
m-Trifluoromethylphenyl, JWH-363
m-Nitrophenyl, JWH-293
67
53
6
2
1
4
5
5
39
23
2
1
16
70
9.1 0.7
16
71
41
1
1
4
245
100
para-isomers
p-Methylphenyl, JWH-244
p-Ethylphenyl, JWH-364
p-Butylphenyl, JWH-371
p-Methoxyphenyl, JWH-243
p-Fluorophenyl, JWH-308
p-Chlorophenyl, JWH-245
p-Trifluoromethylphenyl, JWH-348
130
34
6
3
1
18
29
64
41
33
25
53
1
1
2
3
2
2
1
42
285 40
41
276
1
4
218 19
Suzuki coupling of 7, R = C5H11 with four substituted
arylboronic acids (p-methoxyphenyl, p-methylphenyl, p-
chlorophenyl, and m-chlorophenyl) under the conditions
used for the preparation of JWH-156, (5, R = C3H7) and
JWH-150 (5, R = C4H9) gave poor (10–26%) yields of
pyrroles 6. A modified Suzuki procedure reported by Ba-
done, which employs Pd(OAc)2, tri-o-tolylphosphine,
and K2CO3 in aqueous toluene with a phase transfer cat-
alyst,16 was used to prepare 19 additional substituted pyr-
roles in yields of 24–83%. With one exception these
compounds were synthesized using commercially avail-
able boronic acids, however o-butylphenylboronic acid
is not commercially available and was prepared in four
steps from o-bromobenzaldehyde.15 For purification the
boronic acid was converted to the potassium tetrafluoro-
borate salt.17 Coupling of 7, R = C5H11 with this tetra-
fluoroborate salt was carried out by the modified
Suzuki procedure, with (Ph3P)4Pd as catalyst to give 6,
Ar = o-butylphenyl (JWH-373) in 76% yield.
Others
1-Naphthyl, JWH-309
2-Naphthyl, JWH-347
3-Pyridyl, JWH-366
41
3
49
7
333 17
191 12
169 17
24
1
to electronic effects rather than steric effects. 1-Pentyl-
2-(2-butylphenyl)-4-(1-naphthoyl)pyrrole (JWH-373, 6,
Ar = o-butylphenyl) has decreased CB1 receptor affinity
(Ki = 60 3 nM). This effect is probably due to the steric
bulk of the butyl group. With the exception of the o-tri-
fluoromethylphenyl analog (JWH-372) there is little
difference in the CB1 and CB2 receptor affinities of the
2-arylpyrroles with an ortho-substituted phenyl group.
At the CB2 receptor, JWH-372 is an exception with
greater than 9-fold selectivity for the CB2 receptor.
Other than the meta-fluoro analog (JWH-368, 6,
Ar = m-fluorophenyl, Ki = 16 1 nM) those pyrroles
with a meta-substituted phenyl substituent in the 2-posi-
tion have from somewhat to significantly lower CB1
receptor affinities than the ortho-substituted analogs.
The two compounds with strongly electron-withdrawing
substituents, m-trifluoromethylphenyl (JWH-363) and
m-nitrophenyl (JWH-293) pyrroles, both have very
modest CB1 receptor affinities (Ki = 245 5 nM and
100 5 nM, respectively). The two compounds with
electron-releasing groups (JWH-346 and JWH-367)
and the m-chloro analog (JWH-246) have somewhat
attenuated CB1 receptor affinities relative to the ortho-
substituted compounds. This entire series of pyrroles
with a m-substituted phenyl group in the 2-position
exhibit some (1.7- to 4.4-fold) selectivity for the CB2
receptor.
The affinities of 2-arylpyrroles 6 for the CB1 and CB2
receptors were determined by the same methods that
were employed for the series of 2-phenylpyrroles (5)
and are listed in Table 2.12,13 Those 2-arylpyrroles (6)
with small ortho-substituents on the 2-aryl group
(JWH-370, JWH-365, JWH-292, JWH-307, and JWH-
369) and the unsubstituted analog (JWH-145, 5,
R = C5H11) have uniformly high affinity for the CB1
receptor (Ki = 5.6–29 nM). An exception is the o-trifluo-
romethylphenyl derivative, JWH-372 (6, Ar = o-trifluo-
romethylphenyl), which has Ki = 77 2 nM. The
trifluoromethyl group is inductively a strong electron-
withdrawing substituent with approximately the same
van der Waals radius as a methyl group, Thus, this de-
creased CB1 receptor affinity would appear to be due

J. W. Huffman et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5432–5435
5435
For those pyrroles 6 with a para-substituted phenyl sub-
Acknowledgments
stituent, the compounds with small electron donating
substituents (JWH-244 and JWH-243) as well as the
p-chloro (JWH-245) and p-trifluoromethyl (JWH-348)
analogs have little affinity for the CB1 receptor with
Ki = 130–276 nM. However, the p-ethyl (JWH-244),
p-butyl (JWH-371), and p-fluoro (JWH-308) analogs
have considerably greater and nearly equal affinity with
Ki = 34–42 nM. The CB2 receptor affinities of this group
of 1-pentyl-2-aryl-4-(1-naphthoyl)pyrroles (6) fall in a
relatively narrow range with Ki = 18–64 nM.
The work at Clemson was supported by Grants
DA03590 and DA15340 to J.W.H. and DA15579 to
L.W.P.; that at Virginia Commonwealth University
was supported by Grant DA03672 to B.R.M.
References and notes
1. Lainton, J. A. H.; Huffman, J. W.; Martin, B. R.;
Compton, D. R. Tetrahedron Lett. 1995, 36, 1401.
2. Pertwee, R. G.; Griffin, G.; Lainton, J. A. H.; Huffman, J.
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3. Huffman, J. W.; Dai, D.; Martin, B. R.; Martin, B. R.;
Compton, D. R. Bioorg. Med. Chem. Lett. 1994, 4, 563.
4. Wiley, J. L.; Compton, D. R.; Dai, D.; Lainton, J. A. H.;
Phillips, M.; Huffman, J. W.; Martin, B. R. J. Pharmacol.
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5. Reggio, P. H.; Basu-Dutt, S.; Barnett-Norris, J.; Castro,
M. T.; Hurst, D. P.; Seltzman, H. H.; Roche, M. J.;
Gilliam, A. F.; Thomas, B. F.; Stevenson, L. A.; Pertwee,
R. G.; Abood, M. E. J. Med. Chem. 1998, 41, 5177.
6. Bramblett, R. D.; Reggio, P. H. 1995 Symposium on the
Cannabinoids; International Cannabinoid Research Soci-
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7. Huffman, J. W.; Mabon, R.; Wu, M.-J.; Lu, J.; Hart, R.;
Hurst, D. P.; Reggio, P. H.; Wiley, J. L.; Martin, B. R.
Bioorg. Med. Chem. 2003, 11, 539.
Three examples of pyrroles 6 containing aromatic sub-
stituents at C-2 other than phenyl were also prepared.
The analog with a 1-naphthyl moiety (JWH-309) has
relatively high affinity for the CB1 receptor with
K1 = 41 3 nM, while the 2-naphthyl analog (JWH-
347) has little affinity with Ki = 333 17 nM. The 2-(3-
pyridyl) compound (JWH-366) also has modest affinity
for the CB1 receptor with Ki = 191 12 nM. The pyridyl
(JWH-366) and the 1-naphthyl (JWH-309) compounds
have relatively high affinity for the CB2 receptor with
Ki = 24 1 and 49 7 nM, respectively. The 2-naphthyl
compound (JWH-347) has little affinity for the CB2
receptor (Ki = 169 17 nM).
The enhanced CB1 receptor affinities of pyrroles 5
(R = C5H11 to C7H15) and 6 containing various aryl
substituents, relative to JWH-030 (1, R = C5H11), pro-
vide additional evidence in support of the hypothesis
that cannabimimetic pyrroles as well as their indole
counterparts interact with the CB1 receptor primarily
by aromatic stacking.5–7 In pyrroles 6 a small ortho
electron-releasing substituent slightly enhances CB1
receptor affinity relative to JWH-145 (5, R = C5H11)
with an unsubstituted phenyl group. An inductively
electron withdrawing, but electron releasing by reso-
nance, fluoro or chloro substituent also enhances CB1
receptor affinity.18 Larger or strongly electron-with-
drawing groups attenuate affinity. Other than fluorine
a meta- or para-substituent diminishes CB1 receptor
affinity, however a p-ethyl or p-butylphenyl group has
only a slight effect. This would tend to indicate that
at least some of the decrease in affinity for the meta-
and para-substituted compounds is due to steric effects
inasmuch as a fluorine atom is only slightly larger than
a hydrogen. The variation in CB1 receptor affinities of
pyrroles 6 would appear to be due to a subtle combina-
tion of steric and electronic effects. With the exception
of the 2-naphthyl analog (JWH-347) there is relatively
little variation in CB2 receptor affinities for pyrroles 6,
with Ki = 3.4–71 nM.
8. Korostova, S. E.; Mikhaleva, A. I.; Sobenina, L. N.;
Shevchenko, S. G.; Polovnikova, R. I. J. Org. Chem.
USSR 1986, 436.
9. All target compounds have mass spectral, 1H and 13C
NMR data consistent with the assigned structures. All
compounds were homogeneous to tlc and/or glc and gave
acceptable microanalytical or high-resolution mass spec-
tral data.
10. Chen, W.; Stephenson, E. K.; Cava, M. P.; Jackson, Y. A.
Org. Syn. 1991, 70, 151.
11. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513.
12. Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, R.
K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R. J.
Pharmacol. Exp. Ther. 1993, 265, 218.
13. Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood,
M. E. J. Pharmacol. Exp. Ther. 1996, 278, 989.
14. Knight, L. W.; Huffman, J. W.; Isherwood, M. L. Synlett
2003, 1993.
15. Padgett, L. W. Ph.D. Dissertation, Clemson University,
May 2005.
16. Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.;
Guzzi, U. J. Org. Chem. 1997, 62, 7170.
17. Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.;
Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020.
18. The net electronic effects of aryl halogen substituents are
weakly electron withdrawing.