recent developments in cannabinoid ligands life sci 77 1767 1798 (2005)

Recent developments in cannabinoid ligands

Lea W. PadgettT

Howard L. Hunter Chemistry Laboratory, Clemson University, Clemson, SC, 29634-0973, USA

Abstract

Over the past 40 years, much research has been carried out directed toward the characterization of the

cannabinergic system. With the identification of two G-protein coupled receptors and the endogenous ligand,
anandamide, pharmacological targets have expanded to encompass hydrolase and transport proteins as well as
novel classes of cannabinoid ligands. Those ligands that demonstrate high affinity for the receptors and good
biological efficacy are tied together through lipophilic regions repeatedly demonstrated necessary for activity.
This review presents recent developments in the structure–activity relationships of several classes of cannabinoid
ligands.
D

Keywords: Cannabinoid; Structure–activity relationship; Pyrazole; Aminoalkylindole

Introduction

Marijuana and hashish, derived from the Indian hemp plant Cannabis sativa L., have long been used

as medicinal agents as well as recreational drugs. The primary psychoactive constituent of marijuana was
identified and its structure elucidated in 1964 as D

-tetrahydrocannabinol, 1, (D

-THC,

Fig. 1

) by

Gaoni

and Mechoulam (1964)

. Other compounds exhibiting similar psychoactive effects were subsequently

found, including an endogenous ligand, anandamide, 2 (

Devane et al., 1992

). Identification of these

compounds led to the discovery of two G-protein coupled receptors, CB

, found in the central nervous

0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
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E-mail address: leak@clemson.edu.

Life Sciences 77 (2005) 1767 – 1798

www.elsevier.com/locate/lifescie

system (CNS) (

Matsuda et al., 1990

), and CB

, which is located in the periphery and is interconnected

with the immune system (

Munro et al., 1993; Howlett, 1998; Pertwee, 1997

). These receptors are part of

the endocannabinoid system, which also consists of long-chain polyunsaturated fatty acids such as
anandamide, 2, and 2-arachidonoyl glycerol (2-AG), 3, as well as metabolizing and transport proteins
(

Khanolkar and Makriyannis, 1999

Discovery of the endocannabinoid system has prompted inquiry into the structural features and

biological properties of the receptors. Investigation into the salient structural features of D

-THC

and anandamide has led to the development of several structurally diverse classes of compounds
that bind to the receptors. Development of new ligands in different classes aids in the
determination of the structural requisites for receptor activation. The CB

receptor has been

implicated in several physiological pathways, including the treatment of neuroinflammatory
diseases, psychological and cognitive disorders, and obesity (

Adam and Cowley, 2002; Pertwee,

2000

). The CB

receptor may influence the immune system as it is localized primarily in the

spleen, tonsils, and immune cells (

Martin, 1986

). Structural changes to the ligands permit selective

binding to one receptor subtype, providing controls for developing pharmaceutical agents to target
specific physiological systems.

New compounds are typically evaluated for receptor affinity through in vitro displacement of

radiolabeled ligands with known affinity (

Devane et al., 1988; Compton et al., 1993

). Compounds

showing good receptor affinities can then be evaluated for pharmacological activity and mechanism of
action in a variety of assays. This review focuses on developments since 2002 in ligands that bind with
cannabinoid receptors, both as agonists and as antagonists. New structures and affinity values will be
presented. Ligands that are structurally similar to anandamide and 2-AG (endocannabinoids) will not be
discussed.

NHCH

Fig. 1. Cannabimimetic ligands of different classes.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1768

Traditional cannabinoids

Classical cannabinoids are those containing the tricyclic benzopyran ring system as typified by D

THC. The structure–activity relationship (SAR) data for this class is very diverse and spans a wide range
of functionalities. Although the movement of the double bond in D

-THC to the D

position results in a

slight loss in affinity and a small decrease in potency (

Compton et al., 1993; Busch-Petersen et al.,

1996

), the D

-THC derivatives exhibit in vitro and in vivo effects similar to D

-THC and are

synthetically easier to prepare due to the increased thermodynamic stability of the D

double bond

(

Dalzell et al., 1981

). The receptor interaction model that has been developed points to three primary

sites on the molecule: a C3 aliphatic side chain of at least three carbons; a C1 phenolic hydroxyl group;
and a small C9 substituent, usually consisting of a methyl, hydroxymethyl, or hydroxyl (

Howlett et al.,

1988

). The phenolic hydroxyl has been found not to be essential in certain cases, as the synthesis has

been reported of deoxy derivatives that show excellent affinity for the CB

receptor and some selectivity

for the CB

receptor (

Huffman et al., 1996

). Several analogues that contain cyclic systems have been

prepared and show similar effects (

Reggio et al., 1997

). In depth studies have been made concerning the

nature of the aliphatic side chain. It was shown that a seven-carbon side chain is an optimal length for
affinity (

Edery et al., 1972

). Methylation on the side chain increases potency when close to the aromatic

ring, with the beneficial effects diminishing as the point of substitution moves farther from the ring
system (

Huffman et al., 1995

). Dimethylation to afford 1V, 1V-dimethylheptyl (DMH) is frequently the

side chain of choice due to the high potency of molecules containing this as a functional group and the
ease of DMH synthesis over other dimethyl side chains (

Tius et al., 1995

Quantitative structure–activity relationship (QSAR) studies have demonstrated moderate to high

flexibility in the alkyl side chain, pointing to the necessity of a hydrophobic group, but not elucidating
requirements due to bulk (

McAllister et al., 2002

). Side chains with restricted rotation have been

synthesized to determine how much flexibility is required, see

Table 1

. The introduction of 1V double and

triple bonds results in a moderate increase in affinity, where the cis configuration was favored over the
trans (

Busch-Petersen et al., 1996

). Effects arising from unsaturation farther down the side chain are

varied and in vivo effects do not necessarily correlate with in vitro affinities (

Ryan et al., 1995

). Poor

affinity for the CB

receptor arises from formation of a ring between the side chain and the C2 position

resulting in a rigid analogue with the side chain forced to project laterally out from the ring system
(

Huffman and Yu, 1998; Lu et al., 1997

). When the side chain is conformationally restricted to project

from the bottom face of the molecule, good affinity is exhibited (

Khanolkar et al., 1999

). Computational

studies suggest that the chain must be able to wrap around in proximity of the phenolic ring (

Keimowitz

et al., 1999

To examine the ligand binding pocket of the cannabinoid receptors, analogues containing rings on the

side chain that do not connect back to the benzene ring have been synthesized. The addition of a
dithiolane to the benzylic position affords a ligand with high affinity for both receptors that is
comparable to the 1V,1V-dimethylheptyl derivative, (9) (

Table 1

) (

Papahatjis et al., 1998

). Similarly, the

addition of a cyclopropyl group in the benzylic position affords compounds with high affinity (10).
Functionalization of the cyclopropyl group with gem-dichloro (11) results in slight selectivity for the
CB

receptor, while the bulkier gem-dibromo (12) substitution provides compounds that show equally

high affinity for both receptors (

Papahatjis et al., 2002

A series of cyclic derivatives was synthesized to examine the size of the pocket into which the side

chain fits. Side chains with 5, 6, and 7 atoms now arranged as a cyclic system were synthesized and

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1769

Table 1
Classical cannabinoid ligands

(nM

)

Number

n–heptyl

1',1'–dimethylheptyl

X = H
X = Cl

X = Br

n = 1
n = 2

( )n

n = 3
n = 1
n = 2

( )n

n = 3

X = CH

X = O
X = H

X = SCH

1 3

R1 = H
R1 = C

R1 = C

47.6

c, d

28.5

b, e

0.83

0.44

0.07

c, h

1.27

0.27

c, h

0.71

0.21

c, h

0.34

0.04

b, e

0.57

0.05

b, e

0.94

0.05

b, e

9.49

2.42

b, e

1.86

0.71

b, e

1.76

0.56

b, e

12.3

0.61

b, i

297

10.6

b, i

67.6

2.90

b, i

17.3

0.33

b, i

0.45

0.07

c, j

32.3

4.0

c, j

0.52

0.11

c, j

56.9

6.8

c, j

1.8

0.7

c, j

168

c, j

0.32

c, k

0.85

0.02

b, e

39.3

c, d

25.0

b, e

0.49

0.86

0.16

c, h

0.29

0.06

c, h

1.0

0.36

c, h

0.39

0.06

b, e

0.65

0.04

b, e

0.22

0.01

b, e

2.74

1.10

b, e

1.05

0.41

b, e

6.62

0.92

b, e

0.91

0.08

b, i

23.6

1.76

b, i

85.9

0.31

b, i

17.6

1.03

b, i

1.92

0.4

c, j

19.7

2.7

c, j

0.22

0.06

c, j

257

c, j

3.6

1.3

c, j

103

c, j

0.52

c, k

0.58

0.03

b, e

∆

8–

THC

7
8
10
11
12

13
14
15
16
17
18

19
21
22
20

27
9
29

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1770

affixed to the C1V position to restrict the orientation and flexibility of the side chain (13–18) (

Nadipuram

et al., 2003

). The disubstitution of the C1V position with a dithiolane or dimethyl was retained to limit

rotation around the C3–C1V bond. The cyclohexyl dithiolane compound (17), while exhibiting good
affinity, shows a decrease in receptor affinity with the cyclic group present relative to the same length
straight carbon chain (9). The cyclic dimethyl analogues (13–15) demonstrate similar affinities within
the series and when compared to the DMH side chain (8), implying that the decrease in affinity of the
dithiolane series may be due to steric effects.

An additional series was synthesized examining the placement of an aromatic moiety on the

cannabinoid side chain. A phenyl ring replaced the cyclohexyl group of the previous series and was
connected to the tricyclic ring system by a methylene, dithiolane, dimethyl, and ketone at the C1V
position (19–22) (

Krishnamurthy et al., 2003

). This series preserves the size and mobility restrictions of

the cyclohexyl analogue but significantly changes the electronic effects. The dimethyl compound (19)
shows good affinity with selectivity for the CB

receptor. This is in contrast to the cyclohexyl derivative

(14), which demonstrates no selectivity for receptor subclass. The dithiolane (20) was unselective and
showed less affinity than its aliphatic partner (17). The presence of the ketone moiety (21) affords good
selectivity for the CB

receptor, but this compound as well as the methylene compound (22) have lower

affinities on all counts when compared with D

-THC (6).

A series of D

-THC analogues with rings at the benzylic position was produced (

Papahatjis et al.,

2003

). Cyclopropyl and dithiolane systems (9–10) have already been described. A cyclopentyl (23) and

dioxolane (25) functionality were each synthesized and show good affinity for both receptors with a mild
selectivity for the CB

subtype. Enlargement of the ring to a six-membered dithiane (28) decreases the

affinity slightly and shows a mild selectivity for the CB

receptor. The five-membered dithiolane without

the hexyl group attached (27) shows a marked decrease in affinity for both receptors. Increasing the bulk
of the dithiolane to contain vicinal dimethyl or benzodithiolane moieties also results in a decrease in
affinity (24, 26). The CB

receptor shows greater susceptibility to the steric bulk of the substituents,

implying a greater steric limitation in the binding pocket of this receptor.

Bicyclics

While attempting to simplify the cannabinoid structure necessary for binding, the group at Pfizer

synthesized a number of bicyclic cannabinoid ligands that lack the pyran ring of traditional cannabinoids
(

Little et al., 1988

). The prototypical compound for this class of non-classical cannabinoids is CP-

55,940, (4,

Fig. 2

), a compound now used for radiolabeled displacement assays. It has been shown that

the aliphatic side chain and the phenolic hydroxyl are necessary for affinity, but the removal of the
cyclohexyl hydroxyl affords decreased affinity, and the removal of the cyclohexyl ring results in a
complete loss in affinity (

Howlett et al., 1988

Notes to Table 1:

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean.

Data collected with cell membranes from HEK293 cells transfected with the

human CB

cannabinoid receptor and membranes from CHO-K1 cells transfected with the human CB

cannabinoid receptor.

Affinity determined using rat brain (CB

) or mouse spleen (CB

) membranes.

Busch-Petersen et al. (1996)

Nadipuram et al.

(2003)

Huffman and Yu (1998)

Khanolkar et al. (2000)

Papahatjis et al. (2002)

Krishnamurthy et al. (2003)

Papahatjis et

al. (2003)

Papahatjis et al. (1998)

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1771

Based on a proposed alignment similar to that suggested by

Tong et al. (1998)

, Huffman designed a

pyridone ligand (31) where the benzenoid ring of CP-55,940 was replaced with a heterocycle and the
side chain was an n-pentyl like that found on D

-THC (

Huffman et al., 2001

). Although it was believed

that this compound would serve as a rigid analogue of anandamide, both stereoisomers (9h-OH, JWH-
168; 9a-OH, JWH-183) prepared demonstrated poor affinity for the CB

receptor subtype. The poor

affinity may arise from the inability of the amide carbonyl to substitute for a phenolic hydroxyl, since
CP-47,497 (30) is structurally very similar and possesses very good affinity. These two compounds may
not be good models for anandamide, or it may be a different conformation that gives rise to biological
activity. These compounds do, however, exhibit good CB

selectivity, and may demonstrate salient

features for a binding profile at the peripheral receptor subtype as the removal of the phenolic hydroxyl
of D

-THC also results in increased CB

selectivity.

Cannabidiol (54), a naturally occurring compound in the Marijuana plant, is also bicyclic, but has

poor affinity for CB

and does not exhibit the same in vivo profile. In an effort to determine why this is

the case,

Wiley et al. (2002)

prepared a number of resorcinols on the cannabidiol template (

Table 2

These compounds demonstrate many of the same trends shown by other classes of ligands. The single
most significant feature is the lipophilic side chain, which can vary in length and branching. The C3 side
chain has been demonstrated to be necessary for high CB

affinity in the traditional cannabinoid series

and with anandamide and in the indole series (

Seltzman et al., 1997

). Those compounds shown in

Table

without a dimethylheptyl side chain (43, 52) demonstrate reduced affinity for the CB

receptor

corresponding to the degree of difference between the side chain and the preferred DMH. The CB

affinities are affected, although to a lesser degree. This is in accordance with data that show that greater
CB

affinity is retained over a range of side chains in the D

-THC series (

Huffman et al., 1999

In the cannabidiol series, the C2 resorcinol substituent was also important for determining receptor

binding. The standard substituent at this position is a cyclohexyl group (33), originally chosen because
of the C ring in the traditional cannabinoids. Decreasing the size of this ring to a cyclopentyl results in a
decrease in affinity (32). Increasing the ring size to a cycloheptyl or adamantyl group (34, 35) provides a
small increase in affinity. The addition of a heteroatom to the ring results in a significant decrease in
affinity (36, 37), and in the case of nitrogen (38), a total loss of affinity for both receptors and the loss of
all in vivo activity. Hydrocarbon additions to this ring also result in a small to moderate decrease in
affinity (40–42) compared to 33, although 44 shows a slight increase in affinity. As has been seen in the
D

-THC and anandamide series (

Showalter et al., 1996; Compton et al., 1993

), unsaturations often result

in a decrease in affinity (39).

DMH

-168, 183

CP-55940

CP-47497

JWH

Fig. 2. Bicyclic ligands.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1772

Table 2
Resorcinol derivatives (

Wiley et al., 2002

)

Affinty, K

(nM)

Number

cyclopentyl

cyclohexyl

cycloheptyl

adamantyl

n = 2

153

( )n

n = 1

138

> 10,000

1–cyclohexenyl

2–methylcyclohexyl

4–methylcyclohexyl

4–phenylcyclohexyl

144

3–methylcyclohexyl

Dimethylbutyl

3,3–dimethylcyclohexyl

0.3

3–methylcyclohexyl

> 10,000

5820

662

1990

7515

721

> 10,000

OH
OH
OH
OH
OH
OH

OH
OH
OH
OH
OH
OH
OCH

OCH

DMH
DMH
DMH
DMH
DMH
DMH

DMH

DMH
DMH
DMH
DMH

DMH
DMH
DMH

DMH

3201

141

0.4

1.5

0.1

0.2

0.8

5424

1103

0.3

0.9

0.3

0.01

466

110

> 10,000

911

116

342

105

101

161

> 10,000

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from CHO-

K1 cells transfected with the human CB

cannabinoid receptor.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1773

Methylation of the phenols provides compounds with no appreciable CB

affinity and that are

selective (45–47). This effect has been observed previously in the D

-THC series when there is

no free phenolic hydroxyl (

Huffman et al., 1999

). The CB

affinity of these compounds was

increased by the addition of a tertiary alcohol in the position where the resorcinol is attached (48,
49, 53). Additional substitution to the cyclohexyl ring did not produce any significant beneficial
effects (50–52) and the incorporation of an oxygen atom into the ring structure greatly attenuated
affinity (46–48).

Although cannabidiol is not itself a psychoactive compound and shows poor affinity for the

cannabinoid receptors, it has been shown to act as an antagonist against WIN-55212-2 and CP-55940

Table 3
Cannabidiol derivatives (

Thomas et al., 2004

)

Number

54, ( )-CBD

4.9 AM

CQC(CH

)

114 nM

OCH

N 10 AM

OCH

N 10 AM

58 Abnormal-cbd

N 30 AM

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the

mean of three values with standard error of mean. Affinity determined using mouse brain membranes.

Offertaler et al. (2003)

Table 4
Two enantiomeric classical cannabinoids (

Thakur et al., 2002

)

Stereochemistry

Affinity K

(nM)

59, 6R, 6aS, 9S, 10aS

94.82

124.80

60, 6S, 6aR, 9R, 10aR

0.16

1.15

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the

mean of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from

CHO-K1 cells transfected with the human CB

cannabinoid receptor.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1774

(

Pertwee et al., 2002

). It does this in a manner that implies an as yet undetermined interaction

mechanism, as the antagonism occurs at concentrations far below its binding values (

Pertwee et al.,

2002

). Recent investigations by

Thomas et al. (2004)

are directed at determining the mechanism

through which this antagonism occurs. Four compounds, shown in

Table 3

, were developed and

tested in the mouse vas deferens protocol and evaluated for K

values against [

H]CP55940. It was

determined that these changes were sufficient to point to possible therapeutic targets, as subtle
changes resulted in dramatic differences in ability to antagonize WIN-55212-2 in the mouse vas
deferens assay and to attenuate contractions induced by phenylephrine, the a

-adrenoceptor agonist.

As each molecule gives different results on these tests, it is likely that more than one mechanism is at
work. The antagonism of WIN-55212-2 is competitive, but does not appear to act through direct
competition for the CB

binding site. More work is required to determine what mechanisms are

taking place, how to improve the selectivity, and if the cannabidiol derivatives are functioning as
neutral antagonists.

Two enantiomeric hybrid cannabinoids have been prepared (59–60) that demonstrate a

stereochemical preference in binding (

Thakur et al., 2002

). These compounds and their affinities

for both receptor subtypes are shown in

Table 4

. These compounds have the southern aliphatic

hydroxyl of CP-55940, but are conformationally restricted due to the pyran ring and the unsaturation
of the alkyl chain.

Aminoalkylindoles and related compounds

While searching for non-steroidal anti-inflammatory drugs (NSAIDs) the Sterling-Winthrop group

prepared a group of compounds that inhibit adenylate cyclase activity, are antinociceptive, and are not
blocked by naloxone (

Bell et al., 1991

). The lead compound in this series was pravadoline (61,

Fig. 3

)

and other compounds were developed with increased cannabinoid potency such as WIN-55,212-2 (5),
but with the cost of NSAID efficacy (

Compton et al., 1992

). A detailed review of the

aminoalkylindole (AAI) SAR has been previously presented (

Huffman, 1999

). The salient structural

features for this class are a C3 naphthoyl group and a lipophilic group attached to the indole nitrogen,

OMe

Pravadoline

JWH-161

122

HU-210

123

Fig. 3. Cannabinoid ligands.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1775

although the aminoalkyl group can be replaced with an alkyl group of suitable length with no loss in
affinity (

Wiley et al., 1998; Huffman et al., 1994; Kumar et al., 1995

). It has been proposed that AAIs

interact with the receptor differently than the classical cannabinoids (

Song and Bonner, 1996

). The

carbonyl, believed to be necessary for hydrogen-bonding, has been demonstrated unnecessary through
the synthesis of cannabimimetic indenes (

Reggio et al., 1998

). A model wherein AAIs bind to the

cannabinoid receptor through aromatic stacking has been advanced and is well supported by
computational data (

Reggio et al., 1998

). Experimental evidence shows a decrease in affinity for

pyrroles, which do not contain the benzenoid moiety, in relation to the corresponding indoles (

Lainton

et al., 1995

Working within these hypotheses, several indoles have recently been prepared to examine the

effect of hydrogen-bonding sites on the receptor affinity of ligands. A series of 3-(1-
pentylindole)-1-naphthylmethanes and their corresponding 2-methyl analogues have been produced
by

Huffman et al. (2003)

containing no sites for hydrogen-bonding interaction, shown in

Table

. The 3-(1-pentylindole)-1-naphthylmethane (62) and its 4-methyl-naphthyl (63) and 4-

Table 5
3-Substituted indoles (

Huffman et al., 2003

)

(nM)

OCH

151

127

OCH

323

0.69

0.05

OCH

1.2

0.1

9.5

4.5

5.0

2.1

OCH

4.5

0.1

(nM)

2.9

2.6

1.2

12.4

2.2

2.9

2.6

0.73

0.03

1.9

0.3

113

OCH

Number

63, JWH–184

62, JWH–175

64, JWH–185
65, JWH–196
66, JWH–194
67, JWH–197
68, JWH–018
69, JWH–122
70, JWH–081
71, JWH–007
72, JWH–149
73, JWH–098
74, JWH–116
75, JWH–195
76, JWH–192
77, JWH–199
78, JWH–200
79, JWH–193
80, JWH–198

H
H
H

H
H
H
H
H
H

OCH

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from CHO-

K1 cells transfected with the human CB

cannabinoid receptor.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1776

methoxynaphthyl (64) analogues show receptor affinities that are the same within the limits of
experiment (K

= 17–23 nM). This is slightly less affinity than the corresponding naphthoyl

analogues (68–70). The 2-methyl analogues containing the carbonyl (71–73) differ only slightly
from the non-methylated indoles (68–70), but the 2-methyl analogues of 3-(1-pentylindole)-1-
naphthylmethane (65–67) exhibit greatly reduced receptor affinity. Modeling studies indicate that
this difference may arise from a disruption of aromatic stacking interactions by the 2-methyl
group orienting the halves of the indole molecule into a non-active conformation. The ability of
the naphthoyl groups to hydrogen bond can account for the small decrease in affinity for the 3-
(1-pentylindole)-1-naphthylmethane series relative to the naphthoyl series, but the relatively high
affinity shown by these compounds even in the absence of hydrogen bonding substituents
supports the hypothesis that aromatic stacking is the more important interaction mechanism.
Replacement of the pentyl group with a morpholinoethyl group (75–80) to add additional
hydrogen bonding sites results in compounds that have moderate to good affinities for the
receptor. However, the pentyl group still provides compounds with greater affinities. Modeling
results support the chain length experimentally found to be preferred, namely 4–6 carbons in the
alkyl chain, with the maximum occurring at the pentyl. A hydrophobic pocket has been
postulated that requires at least three carbons to interact but lengthening the chain to seven
carbons results in a van der Waals overlap. Aromatic residues are arranged near the hydrophobic
pocket in such a way as to prefer the s-trans ligand conformation around the indole–naphthoyl
bond. The presence of a 2-methyl group in the absence of a carbonyl creates a strong energetic
preference for the s-cis conformer resulting in the observed loss of affinity.

It has been demonstrated that the presence of a 7-methyl group on the naphthoyl substituent does

not significantly affect the affinity of N-pentyl-3-(1-naphthoyl)indole (

Aung et al., 2000

). New

indoles have been prepared to expand on the known SAR concerning substituted 3-naphthoyl
groups. A series of alkyl substituted indoles has recently been prepared by Huffman et al.
(unpublished data) and the data are presented in

Table 6

. The addition of an ethyl or propyl

substituent to the four position of the naphthoyl in both N-propyl- and N-pentylindole series (85,
86, 96, 97) results in an increase in affinity for both receptors compared with 68 and 83. In the N-
propyl series a 4-butylnaphthoyl substituent results in an increase in affinity (87), but provides a
decrease in the N-pentyl series (98), although this compound still possesses high affinity. For the N-
propylindoles, addition of a methyl group in the seven-naphthoyl position (81) results in a five-fold
increase in CB

affinity, and an ethyl group (93) gives a three-fold increase. Both substituents

afford an increase in CB

receptor affinity. If the indole has a 2-methyl substituent, however,

substitution at the 7-naphthoyl position to give 82 results in a decrease in affinity when compared
with 88. Substitution in the seven-naphthoyl position appears to have no significant effect on
receptor affinity in the N-pentyl series.

Indoles, shown in

Table 7

, have been synthesized to evaluate the effects of 2, 4, 6, and 7-alkoxy-1-

naphthoyl substituents on receptor affinity. Substitution in the 4 position with methoxy or ethoxy
generally increases the receptor affinity for CB

in both the N-pentyl (70, 120) and N-propylindoles

(105, 112). In the presence of the indole 2-methyl group, the affinities decrease for both N-alkyl series
(109, 113, 121), with the exception of analogue 73, which increases slightly. Substitution in the 6
position affords a decrease in CB

affinity, regardless of a 2-methyl group on the indole (106, 110,

115, 118). Groups in the 2 position of the naphthoyl give rise to significant reductions in affinity (104,
108, 114, 117). Substitution at the 7-naphthoyl position resulted in an increase in affinity for 107 and

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1777

116, but a decrease in CB

affinity with the indole 2-methyl (111, 119). Substitution of an alkoxy

group anywhere on the naphthoyl in the presence of the indole 2-methyl group results in a decrease in
CB

receptor affinity. The notable exception to this is again compound 73. In the N-propyl series,

when no 2-methyl substituent is present on the indole, substitution at all positions on the naphthoyl
with an alkoxy group gives rise to increased affinity for CB

. In the N-pentyl series in the absences of

the indole 2-methyl, substitution at any position other than 6-naphthoyl (115) results in a decrease in
CB

affinity. The 2-methyl-3-(2-methoxy-1-naphthoyl)-N-pentylindole analogue (117) also shows

good CB

selectivity and has a moderate affinity. This series as a whole provides a significant number

Table 6
3-(Alkyl-1-naphthoyl)indoles (

Huffman et al., 2003

)

Compound

(nM)

81, JWH-076

214 F 11

106 F 46

82, JWH-046

343 F 38

16 F 5

83, JWH-072

1050 F 55

170 F 54

84, JWH-120

1054 F 31

6.1 F 0.7

85, JWH-212

33 F 0.9

10 F 1.2

86, JWH-180

26 F 2

9.6 F 2.0

87, JWH-239

342 F 20

52 F 6

88, JWH-015

164 F 22

13.8 F 4.6

89, JWH-148

123 F 8

14 F 1.0

90, JWH-211

70 F 0.8

12 F 0.8

91, JWH-189

52 F 2

12 F 0.8

92, JWH-241

147 F 20

49 F 7

93, JWH-235

338 F 34

123 F 34

94, JWH-236

1351 F 204

240 F 63

68, JWH-018

9 F 5

2.9 F 2.6

95, JWH-048

10.7 F 1.0

0.49 F 0.1

96, JWH-210

0.46 F 0.03

0.69 F 0.01

97, JWH-182

0.65 F 0.03

1.1 F 0.1

98, JWH-240

14 F 1

7.2 F 1.3

99, JWH-213

1.5 F 0.2

0.42 F 0.05

100, JWH-181

1.3 F 0.1

0.62 F 0.04

101, JWH-242

42 F 9

6.5 F 0.3

102, JWH-234

8.4 F 1.8

3.8 F 0.6

103, JWH-262

28 F 3

5.6 F 0.7

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the

mean of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from

CHO-K1 cells transfected with the human CB

cannabinoid receptor.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1778

of compounds with selectivity for the CB

receptor, although the affinities for many of them are only

moderate.

Pyrroles

As a result of the suggested overlaps of traditional cannabinoids and the aminoalkylindoles

indicating how these two different structural classes interact with the cannabinoid receptors, it was
concluded that the benzenoid moiety of the indole may not be necessary for activity. A series of 3-(1-

Table 7
3-(Alkoxy-1-naphthoyl)indoles

Compound

(nM)

83, JWH-072

1050 F 55

170 F 54

104, JWH-265

OCH

3788 F 323

80 F 13

105, JWH-079

OCH

63 F 3

32 F 6

106, JWH-163

OCH

2358 F 215

138 F 12

107, JWH-165

OCH

204 F 26

71 F 8

88, JWH-015

164 F 22

13.8 F 4.6

108, JWH-266

OCH

N 10,000

455 F 55

109, JWH-094

OCH

476 F 67

97 F 3

110, JWH-151

OCH

N 10,000

30 F 1.1

111, JWH-160

OCH

1568 F 201

441 F110

112, JWH-259

220 F 29

74 F 7

113, JWH-261

767 F 105

221 F14

68, JWH-018

9 F 5

2.9 F 2.6

114, JWH-267

OCH

381 F16

7.2 F 0.14

70, JWH-081

OCH

1.2 F 0.1

12.4 F 2.2

115, JWH-166

OCH

44 F 10

1.9 F 0.08

116, JWH-164

OCH

6.6 F 0.7

6.9 F 0.2

71, JWH-007

1.2 F 0.1

12.4 F 2.2

117, JWH-268

OCH

1379 F 193

40 F 0.6

73, JWH-098

OCH

4.5 F 0.1

1.9 F 0.3

118, JWH-153

OCH

250 F 24

11 F 0.5

119, JWH-159

OCH

45 F 1

10.4 F 1.4

120, JWH-258

4.6 F 0.6

10.5 F 1.3

121, JWH-260

29 F 0.4

25 F 1.9

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the

mean of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from

CHO-K1 cells transfected with the human CB

cannabinoid receptor.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1779

naphthoyl)-alkylpyrroles was prepared to evaluate this hypothesis, and it was determined that the
pyrroles possess less affinity for the cannabinoid receptor than do the corresponding indoles (

Lainton

et al., 1995

). It was also observed that the effect of alkyl chain length on binding affinity is similar to

that observed in the 3-(1-naphthoyl)-alkylindole series where the optimal length is five carbons. The
affinity decreases rapidly as the chain is lengthened or shortened. To expand the SAR concerning
pyrroles, several substituted derivatives have been prepared. A hybrid compound, JWH-161 (122),
combines the traditional D

-THC structure with that of an alkylindole. The high affinity this

compound shows for CB

= 19 F 3 nM) provides a model for the directed substitution of the

pyrrole nucleus (

Huffman et al., 2000

A computational overlay of JWH-161 (122) and a number of pyrrole derivatives target the distal ring of

the naphthoyl moiety, the a-positions of the pyrrole, and the alkylhydroxy substituent of the potent
cannabinoid HU-210 (K

= 0.73 F 0.11) (123) as prime sites for further investigation (

Huffman et al.,

2000

). Several new ligands are shown in

Table 8

(

Tarzia et al., 2003

). The concomitant presence of methyl

substituents at both a-positions of the pyrrole (125) results in a moderate decrease in affinity for the CB

Table 8
Pyrrole cannabinoid analogues (

Tarzia et al., 2003

)

Number

Affinity K

(nM)

rCB1

hCB2

124

1-naphthyl

30.5 F 4.7

552 F 314

125

1-naphthyl

45.3 F 7.5

9.85 F 2.1

126

1-naphthyl

N 1000

309.7 F 20.8

127

pClC

1-naphthyl

83.7 F 17.8

55.6 F 26.5

128

1-naphthyl

13.3 F 0.5

6.8 F 1.0

129

1-naphthyl

780 F 326

691.3 F 101.3

130

pClC

1-naphthyl

38 F 7.2

194.5 F 27.5

131

1-naphthyl

(CH

)

235.8 F 6.2

139 F 55

132

N 1000

133

N 1000

134

pClC

N 1000

135

HO(CH

)

N 3000

N 10,000

136

o(CH

CO)C

367.3 F 31.2

N 1000

137

c-C

415.5 F 79.5

483.5 F 211

138

1-naphthyl

11.6

139

1-naphthyl

40.83 F 3.32

49.2 F 7.1

140

1-naphthyl

2-naphthyl

333.7 F 17.0

169.3 F 17.0

Data from displacement of [

H]WIN55212-2 in at least three independent experiments run in duplicate and expressed as the

mean of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from

CHO-K1 cells transfected with the human CB

cannabinoid receptor.

Knight et al. (2003)

Knight et al. (2004)

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1780

receptor and a large increase in affinity for the CB

receptor when compared to 3-(1-naphthoyl)-N-

pentylpyrrole (124). This characteristic is also demonstrated in several other ligands, although the effect is
less significant (127, 128, 130). The addition of a bromine atom to the 4-position of the pyrrole also results
in a small increase in affinity for CB

and a large increase in affinity for the CB

receptor (128). The

addition of a cyclohexyl ring connecting the 4 and 5 position greatly reduces CB

affinity (131), however,

even though it is assumed to occupy the same location as the benzenoid moiety of the corresponding
indoles. As with the indoles, addition of a propyl chain to the nitrogen in place of a pentyl group results in
significantly attenuated affinity for CB

(126) or both receptor subtypes (129), although in some cases it

provides a degree of CB

selectivity, a trend that has been previously observed (

Wiley et al., 1998

). The

successful substitution of a para-chlorobenzyl substituent (127, 130) to the nitrogen yielding compounds
with moderate affinity is unexpected in light of the bulk of evidence for a lipophilic binding pocket of finite
size. The para-chlorobenzyl substituent with a benzoyl instead of a naphthoyl gives a compound with no
affinity for either receptor (134). These compounds may interact with the receptor through a different
mechanism, although there exists little evidence on which to base a hypothesis at this time.

Alterations to the 3-aroyl substituent provide compounds with dramatically attenuated potency,

speaking strongly for the distal naphthyl ring interacting directly with the ligand binding pocket
(

Tarzia et al., 2003

). The use of a benzoyl substituent gives compounds with no appreciable affinity

(132–134). The compounds that have structural features such that an aliphatic ring may occupy the
same spatial location as the naphthyl ring, and thus the cyclohexene ring of D

-THC, still show some

binding potential, although it is greatly reduced. This is demonstrated by N-(2-acetylphenyl)
carboxamido and N-cyclohexyl carboxamido groups (136, 137). The addition of a propanol
substituent (135) to mimic the northern aliphatic hydroxyl on many traditional cannabinoids was
also performed in an effort to target the binding site that the traditional cannabinoids appear to utilize.
This compound exhibited no appreciable affinity, indicating that this may not be an important binding
interaction, at least for the pyrroles. This lends support to the belief that the pyrroles bind with the
receptor in a mode different to that of the traditional cannabinoids.

While the proposed alignment (

Huffman et al., 1994

) does not indicate the benzenoid moiety of the

indoles as essential to binding, its removal results in a decrease in potency. Indeed, if the AAIs interact
primarily through aromatic stacking by a different mode than that of the traditional cannabinoids, this
ring may play a less obvious but essential role. To probe the decrease in affinity, a series of pyrroles has
been prepared that replace the fused benzenoid moiety with a conformationally flexible aromatic ring in

SR141716

141

SR144528

142

143

Fig. 4. Pyrazole antagonists and phenyl analogue.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1781

the 2-position of the pyrrole nucleus. The addition of a phenyl substituent (138) affords a compound
with CB

affinity comparable to that of 3-(1-naphthoyl)-N-pentylindole (124) (

Knight et al., 2003

Derivatization of the phenyl substituent provides compounds with a range of affinities, which, when
taken with compound 138, points to more than electronic effects for determining receptor interaction.
Replacement of the phenyl with 1-naphthyl (139) results in a 5-fold decrease in affinity, but substitution
with 2-naphthyl (140) results in a 43-fold decrease in affinity for CB

. The drop in affinity between these

three compounds is likely due to steric limitations in the binding pocket, but no docking studies have
been performed to support this hypothesis.

Table 9
Selected pyrazole analogues (

Wiley et al., 2001

)

Number

(nM)

141 SR141716

4–Clphenyl

144

4–Clphenyl

145

4–Clphenyl

146

4–Clphenyl

147

4–Clphenyl

148

4–Clphenyl

149

4–Clphenyl

150

4–Clphenyl

151

N–(piperidin–1–yl)–amido

152

N–(piperidin–1–yl)–amido

6.2

167

657

422

2.1

0.08

233

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean. Affinity determined using rat brain homogenate.

Thomas et al. (1998)

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1782

Diarylpyrazoles

The search for cannabinoid receptor antagonists was largely unsuccessful until the development of

a new family of ligands by the Sanofi group in 1994 (

Rinaldi-Carmona et al., 1994

). This class is

based on a diarylpyrazole, of which SR141716 (141,

Fig. 4

) is the archetype. This compound is

selective for the CB

receptor and antagonizes the actions of D

-THC, CP-55940, and WIN-55212-2

in vivo (

Rinaldi-Carmona et al., 1995, 1998

). Early uses of these compounds in pharmacology

testing and initial development of SAR and pharmacophores for these compounds have been
previously reviewed (

Barth and Rinaldi-Carmona, 1999

). Modeling data points to a possible overlap

of the para position on the 5-aryl substituent with the side chain of D

-THC (

Thomas et al., 1998

A series of analogues prepared by

Wiley et al. (2001)

agrees with this alignment, see

Table 9

. These

analogues demonstrate the necessity of the 5-aryl substituent, as the receptor affinity sharply
decreases if this position is substituted with an alkyl chain (152). They also show that replacement
of the amide with a ketone, alkyl, or alkyl ether results in an attenuation of affinity (147, 149, 150).
Interestingly, the substitution of the amide nitrogen with a pentyl or heptyl chain (145, 146) gives
compounds with good affinity that exhibit agonist tendencies in vivo (

Wiley et al., 2001

). A

thorough presentation of the SAR of these compounds has been previously reported (

Howlett et al.,

2002

Studies concerning the effects of structural features employed in the compounds shown in

Table 9

and others shown in

Table 10

(

Bass et al., 2002

) demonstrate that the inverse agonism of SR141716

and the affinity values for the receptor do not correlate with the ability to stimulate locomotor
activity. The synthesis of rigid analogues with an indazole nucleus has provided compounds with
poor affinity that are capable of locomotor stimulation. The compounds described by

Wiley et al.

(2001)

with bulky groups on the 1-phenyl substituent are unable to promote locomotor activity as

are compounds where the carboxyamide piperidine functionality has been replaced with either a
ketone or an alkyl chain exchanged for the piperidine. Sterically hindered groups on the 5-aryl

Table 10
Rigid analogues of SR141716 (

Bass et al., 2002

)

Cl
Br
OH

153
154
155
156

157
158

3533 ± 170

475 ± 6
881 ± 44
592 ± 27

>10,000

1487 ± 99

Number

(nM)

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean. Affinity determined using mouse brain membranes.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1783

substituent do not appear to change the activity, although the 4-methyl substituent of the pyrazole
appears to play a role in determining if the compound will stimulate or depress activity. These
compounds display a wide range of affinities for the receptor, which appears to bear no direct
connection to this particular in vivo effect. An analogue has been prepared wherein the pyrazole is
replaced by a phenyl ring, (143) (

Bass et al., 2002

). This compound shows a decreased ability to

stimulate locomotor activity and has a moderate affinity for the CB

receptor (K

= 113 F 20) relative

to [

H]CP55940.

A study of the effect of the aminopiperidine region on binding and antagonism has been conducted by

Francisco et al. (2002)

. Alkyl, hydroxyalkyl, and alkylhydrazine derivatives of SR141716 were prepared

and their affinities determined against [

H]CP55940, see

Table 11

. This series examines two primary

features: substituent size and the presence of heteroatoms. Relative to SR141716, replacement of the
piperidine nitrogen with a methylene group (164) provides a compound with high affinity and good

Table 11
Amide and hydrizide derivatives (

Francisco et al., 2002

)

141 SR141716

159
160
161
162
163

164

165

166
167
168
169
170
171
172
173

(CH

)

(CH

)4CH

OH
CH

CH2OH

NHCH

NHCH2CH

NH(CH

)

NH(CH

)

5.6

46.3

1.5

29.9

0.6

13.4

1.0

11.4

0.5

18.1

4.0

2.46

0.10

22.9

2.2

1690

480

385

160

374

555

143

74.8

11.5

50.9

6.4

>000

3110

610

2960

2100

1600

430

1110

240

6870

228

2400

780

7820
4270

570

1250

280

12,100

170

6660

930

6061

900

2620

440

2850

160

(nM)

Number

Data from displacement of [

H]CP55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from CHO-

K1 cells transfected with the human CB

cannabinoid receptor.

Rinaldi-Carmona et al. (1994)

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1784

antagonistic behavior. Substitution with a morpholino group (165) results in a decrease in affinity, as
does the presence of a terminal hydroxyl group (166–168). Throughout all the derivatives, affinity
increases as the carbon chain length increases up to pentyl. After this, the affinity begins to decrease
again. This effect is seen even over the addition of the heteroatoms. QSAR studies suggest that
preferential binding occurs when the amide substituent is no more than 3 A

˚ in length and there is a

positive charge density on the substituent (

Francisco et al., 2002

). This computational modeling is

supported by the structure binding data.

Table 12
1,4-Dihydroindeno[1,2-c]pyrazole-based ligands (

Mussinu et al., 2003

)

N(CH

)

(nM)

Number

2050

1268

1570

333

0.5

825

723

1152

363

399

1787

>5000
3035

13.5

798

1881

119

2183

123

2789

>5000

0.34

0.06

0.225

0.02

0.27

0.02

5.5

0.5

0.23

0.036

6.788

0.47

0.385

0.04

0.037

0.003

12.3

0.9

0.09

120

9.9

0.52

144

455

978

>5000

174
175
176
177
178
179
180
181
182
183
184
185

186

187
188

189

190

191

6Cl
6F
6Br
6I
5Cl
7Cl
H
6CH

6OCH

6Cl
6Cl
6Cl

6Cl

6Cl
6Cl

6Cl

2,4 Cl

4 Cl
H
4 OCH

2,4 Cl

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the mean

of three values with standard error of mean. Affinity determined using mouse brain homogenate (CB

) and mouse spleen

membranes (CB

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1785

Another series of rigid diarylpyrazoles was synthesized and shows affinities similar to that of

SR144528 (142), a potent and selective ligand for CB

receptor subtype (

Mussinu et al., 2003

). The

prototypical compound of this system, shown in

Table 12

, is substituted similarly to SR141716 but with

a five-membered ring closed between the 4-position of the pyrazole and the 5-aryl substituent (174).
This compound demonstrates a high potency and selectivity for the CB

receptor. Differences in the aryl

substituent, R, are well tolerated, although a 6-OMe (182) and 6-I (177) substituent results in a decrease
in potency and selectivity, but maintains the trend. Special attention should be paid to the 6-Me
compound (181), which is very potent and has a 9810-fold selectivity over the CB

receptor. Changes to

the 1-aryl pyrazole substituent result in some attenuation of these effects, but maintain the trend.
Exchanging the piperidine of the carboxyamido group for other nitrogen-containing groups results in a
marked decrease in potency and selectivity, although selectivity for the CB

receptor is maintained.

These data suggest that enforcing this rigid conformation on the molecule locks its conformation into
that which is preferred by the CB

receptor, although there is no conclusive evidence presented to

indicate why. These compounds were not evaluated for antagonist activity.

An additional rigid analogue (192) (

Fig. 5

) containing a seven-membered ring as the connection

between the 5-phenyl substituent and the pyrazole of SR141716 was prepared. This compound was
found to have extremely high affinity and selectivity for the CB

receptor in a competitive assay

against [

H]CP55940 (CB

= 350 F 5 fM; CB

= 21 F 0.5 nM), a selectivity of 60,000-fold (

Ruiu

et al., 2003

). This compound, dubbed NESS-0327, was found to inhibit WIN-55212-2 induced

analgesia and antinociception, and also to behave as a competitive antagonist in the mouse vas
deferens assay. As the compound does not itself display antinociceptive action, it may be a true
antagonist and not an inverse agonist, although further study is necessary.

Synthesis of several analogues and their evaluation in comparative molecular field analysis

(CoMFA) modeling studies has been performed by

Shim et al. (2002)

. Steric contour images

demonstrate that both the N1 and C5 pyrazole aryl substituents are of significant consequence for
receptor binding. As was illustrated in some compounds initially presented by

Wiley et al. (2001)

the addition of hydrophobic substituents to these two aryl groups increases affinity for the CB

receptor until a certain size is reached. Then a sharp decrease in affinity seems to indicate that a
steric overlap occurs, exceeding the size of the binding pocket. Simple alkyl chains on the N1
position (195–198) may be able to bend around and mimic the size and shape of the 2,4-
dichlorophenyl substituent, implying an interaction with certain residues. These data, shown in

Table 13

, suggest a superposition of the N1 substituent and the C3 side chain of traditional

Fig. 5. NESS-0327 (192).

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1786

cannabinoids that has been shown to possess a maximum optimal size (

Melvin et al., 1993

). The

5-aryl moiety, which exceeds beyond the superposition with known agonists, may interact with the
receptor and prevent its conformation from changing to the active state. This overlap is in contrast

Table 13
Selected pyrazole analogues (

Shim et al., 2002

)

Number

(nM)

193

2,4-dichlorophenyl

N-(hydroxymethyl)amido

165

194

2,4-dichlorophenyl

N-(morpholin-4-yl)amido

195

n-propyl

N-(piperidin-1-yl)amido

771

196

n-pentyl

N-(piperidin-1-yl)amido

197

n-hexyl

N-(piperidin-1-yl)amido

198

n-heptyl

N-(piperidin-1-yl)amido

199

2,4-dichlorophenyl

(piperidin-1-yl)ethoxymethyl

232

200

2,4-dichlorophenyl

(cyclohexyl)methoxymethyl

100

201

2,4-dichlorophenyl

4-fluorobenzoxymethyl

202

4-n-pentylphenyl

N-(piperidin-1-yl)amido

1360

203

2,4-dichlorophenyl

N-(piperidin-1-yl)amido

n-pentyl

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the

mean of three values. Affinity determined using rat brain homogenate.

Table 14
Cycloalkyl analogues (

Krishnamurthy et al., 2004

)

N N

Number

(nM)

204

p-chlorophenyl

Cyclopentyl

1560 F 77

1020 F 22

205

p-chlorophenyl

Cyclohexyl

351 F1.5

3210 F 45

206

p-chlorophenyl

Cycloheptyl

275 F 67

2197 F 21

207

p-chlorophenyl

3-methylcyclohexyl

494 F 57

281 F11

208

p-chlorophenyl

4-methylcyclohexyl

264 F 26

479 F 50

209

p-methylphenyl

2,4-dichlorophenyl

39 F 2.0

2490 F 102

210

Cyclohexyl

p-chlorophenyl

318 F 8.5

133 F 30

211

Cycloheptyl

p-chlorophenyl

273 F 19

410 F 10

212

Cyclohexyl

cyclohexyl

5110 F 110

N 2.5 10

Data from displacement of [

H]CP-55940 in at least three independent experiments run in duplicate and expressed as the

mean of three values with standard error of mean. Affinity determined using rat brain homogenate (CB

) and membranes from

CHO-K1 cells transfected with the human CB

cannabinoid receptor.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1787

to that presented by

Thomas et al. (1998)

, in which the C5 aryl group is overlaid with the C3 side

chain. Both models stress the importance of the 4-chloro group as an extension beyond the
molecular volume shared with agonists, and assign one aryl group to be the antagonist-conferring

Table 15
Diaryldihydropyrazole derivatives (

Lange et al., 2004

)

Number

(nM)

213

4-CH

4-Cl

197 F 152

214

4-Cl

16.1 F 6.6

215

4-OCH

4-Cl

196 F 107

216

2,4,6-(CH

)

4-Cl

24.2 F 13.0

217

4-F

4-Cl

52.6 F 10.5

218

4-CF

SCH

4-Cl

16.6 F 11.6

219

4-Cl

N(CH

)

4-Cl

280 F 178

220

4-F

N(CH

)

4-Cl

N1000

221

2-Cl

NHCH

4-Cl

75.4 F 12.3

222

3-Cl

NHCH

4-Cl

13.9 F 7.9

223

4-CF

NHCH

4-Cl

221 F130

224

4-Cl

NHCH

4-Cl

25.2 F 7.4

225

4-F

4-Cl

NHCH

4-Cl

584 F 220

226

4-Cl

NHCH

4-F

214 F 55

227

4-Cl

NHCH

4-Cl

255 F 105

228

NHCH

4-Cl

170 F 44

229

4-F

NHCH

4-Cl

338 F 170

230

4-CH

NHCH

4-Cl

119 F 40

231

3-CF

NHCH

4-Cl

36.5 F 21.7

232

2,4,6-(CH

)

NHCH

4-Cl

54.2 F 17.7

233

4-OCH

NHCH

4-Cl

22.9 F 11.0

234

3,4-benzo

NHCH

4-Cl

21.8 F 3.4

235

4-CF

NHCH

4-Cl

35.9 F 10.8

236

4-CF

NHCH

4-Cl

293 F 120

237

4-Cl

NHCH

4-Cl

7.8 F 1.4

238

4-Cl

NHCH

4-Cl

894 F 324

Data from displacement of [

H]arachadonic acid in at least three independent experiments run in duplicate and expressed as

the mean of three values with standard error of mean. Affinity determined with CHO-K1 cells overexpressing the human
cannabinoid receptor.

( )-Enantiomer.

(+)-Enantiomer.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1788

group. A comparison of the affinities for compounds 202 and 203 implies that the N1 group is
more sterically restricted, since an alkyl extension in this position resulted in a significant loss of
affinity.

Based on the findings that the N1 substituent does not have to be an aromatic ring to maintain

appreciable receptor affinity and that cyclohexyl groups can be isosteric to phenyl rings in biological
systems (

Hashimoto et al., 2002

), a series of pyrazoles with cycloalkyl groups in the C5 and N1

positions were prepared and evaluated for receptor affinity, shown in

Table 14

(

Krishnamurthy et al.,

2004

). The replacement of these aryl groups was detrimental to receptor affinity for both subtypes.

Only the C5 p-methylphenyl substituent showed any significant binding affinity and there
appears to be no consistent selectivity for receptor subtype within this series.

A new series of 3,4-diarylpyrazolines has been developed loosely based on the structure of

SR141716 (

Lange et al., 2004

). A significant number of derivatives have been synthesized in an effort

to develop a useful SAR picture of this ligand class, shown in

Table 15

. Several key features in this

series present themselves. Those compounds with good CB

affinities also generally present

antagonistic effects when evaluated in vivo for CP55940 induced hypotension and WIN-55212-2
induced hypothermia. All of the compounds tested for CB

affinity had K

values of 1000 nM or

greater. Affinity is increased when the aryl sulfonyl group is substituted with a halide in the 4 position
(214, 217) or is substituted with three methyl groups in a 2,4,6 pattern (216). Higher affinity was
obtained when the amidine possessed at least one hydrogen atom (in an NH

or NHCH

functionality). The presence of one methyl group significantly increases bioavailability. X-ray
crystallography of one potent analogue showed the positioning for an intramolecular hydrogen bond
between the amidine hydrogen and the N2 of the dihydropyrazole. Molecular modeling calculations

Table 16
Selected pyrazole derivatives (

Dyck et al., 2004

)

Number

(nM)

239

3-Azabicyclo[3.3.0]octan-3-yl

5 F 1

240

Cyclohexyl

100 F 32

241

1-Homopiperidinyl

14 F 5

242

CH(Me)CHMe2

41 F 3

243

2-(4-Fluorophenyl)ethyl

91 F 35

244

4-Pyridyl

85 F 5

245

2-(Dimethylamino)ethyl

(70%)

Measuring displacement of [

H]CP-55,940 from HEK EBNA cells expressing human CB

receptor. Data from three

independent experiments expressed as the mean of three values with standard error of mean.

Percent inhibition at 20 AM.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1789

also indicate the presence of this interaction in a low-energy conformation of the molecules. X-ray
crystallography also indicated that the absolute configuration of the 4-position was 4S. Both the R and
S stereoisomer were resolved for two potent ligands, and it was determined that the R isomers (236,
238) exhibited significantly lower affinity for the receptor and displayed no activity in vivo. This
demonstrates a distinct stereospecificity in the receptor–ligand interaction.

With the exception of 143, the SR141716 analogues discussed so far have been designed on a pyrazole

nucleus. Three new series by

Dyck et al. (2004)

begin to examine the impact of the pyrazole ring, whether

as a scaffold or as an essential part of the receptor interaction. Selected pyrazoles were synthesized to
evaluate the effects of certain amide substituents on receptor affinity. The receptor affinities for these
compounds are shown in

Table 16

. These data are consistent with those already reported. Replacement of

the hydrazine with a simple amine results in a reduction in affinity. Disubstitution of the amide nitrogen
also results in lowered affinity (240). Polar substituents in this region are not well tolerated. The slightly
larger bicyclooctyl group (239), however, gives a slightly increased affinity over the piperidyl substiutent
of SR141716.

A series of triazoles with similar amide substituents was synthesized, see

Table 17

. These

compounds as a whole demonstrated lower affinities for the receptor than the pyrazoles. It is believed
that the absence of the C4 methyl group may be the cause for this. An attempt to spatially occupy the
site of the absent methyl group by adding ortho-substituents to the neighboring aryl group was
unsuccessful, instead resulting in a further loss of affinity (252–256). The isomeric orientation of the

Table 17
Selected triazole derivatives (

Dyck et al., 2004

)

Number

(nM)

246

3-Azabicyclo[3.3.0]octan-3-yl

137 F 35

247

4-Methylcyclohexyl

95 F 34

248

1-(4-Chlorophenyl)ethyl

66 F 17

249

1-Indanyl

101 F 34

250

2-(Dimethylamino)ethyl

(49)

251

1-Benzylpyrrolidin-3-yl

29 F10

252

3-Azabicyclo[3.3.0]octan-3-yl

164 F 60

253

1-Homopiperidinyl

(43)

254

N(3-CF

)CH

32 F 5

255

OMe

3-Azabicyclo[3.3.0]octan-3-yl

270 F 5

256

OMe

Isopropyl

350 F 137

Measuring displacement of [

H]CP-55,940 from HEK EBNA cells expressing human CB

receptor. Data from three

independent experiments expressed as the mean of three values with standard error of mean.

Percent inhibition at 20 AM.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1790

triazole ring has little effect on the interaction of the molecule with the receptor. The same trends
regarding amide substituents are seen in the triazoles as were seen in the pyrazoles.

An analogous imidazole series was produced and evaluated for CB

receptor affinity, shown in

Table

. These compounds are less potent than the pyrazoles, but show better affinity than the triazoles. With a

methyl (264, 266), cyano (263), or bromo (262) substituent in the position corresponding to the C4 methyl
of SR141716, the affinities are comparable to the pyrazoles. The presence of a small substituent in this
position seems to be essential for effective binding to occur, although an acetylene group (265) eliminates
the affinity. As can be inferred from previous data, the presence of increasingly lipophilic side chains on
the amide result in an increase in affinity in all three of these series.

A series of hydantoin-based ligands was prepared and evaluated for their receptor affinity and

lipophilicity (

Ooms et al., 2002

). These compounds were first evaluated for their ability to displace

SR141716 at a concentration of 10 AM. Three compounds (272, 273, 275) displaced approximately
90% of the SR141716 and were examined for their affinity for the human CB

receptor against

SR141716. These compounds are shown in

Table 19

. Compounds with aryl substituents other than

bromine displayed a weakened ability to displace SR141716 (267–271). Lipophilicity is not the only
factor in displacement, since many compounds with modest lipophilicity also show good displacement
of SR141716. The compounds tested for CB

affinity also demonstrated neutral antagonist activity.

Table 18
Imidazole derivatives (

Dyck et al., 2004

)

Number

(nM)

257

1-Piperidinyl

85 F 16

258

3-Azabicyclo[3.3.0]octan-3-yl

66 F 11

259

1-Homopiperidinyl

78 F 14

260

Cyclohexyl

48 F 19

261

2-(Dimethylamino)ethyl

(48)

262

3-Azabicyclo[3.3.0]octan-3-yl

11 F 4

263

3-Azabicyclo[3.3.0]octan-3-yl

9 F 1

264

3-Azabicyclo[3.3.0]octan-3-yl

14 F 4

265

3-Azabicyclo[3.3.0]octan-3-yl

CCH

770 F 206

266

1-(4-Chlorophenyl)ethyl

33 F 9

Measuring displacement of [

H]CP-55,940 from HEK EBNA cells expressing human CB

receptor. Data from three

independent experiments expressed as the mean of three values with standard error of mean.

Percent inhibition at 20 AM.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1791

Miscellaneous classes

A novel, CB

selective ligand, JTE-907 (277) (

Fig. 6

) was reported in 2001 (

Iwamura et al., 2001

This compound shows the biological activity of an inverse agonist and good affinity and selectivity for
the human CB

receptor (K

hCB

= 2370 F 297 nM; hCB

= 35.9 F 7.32 nM). This compound is the first

1,2-dihydroquinone-3-carboxyamide reported as a selective cannabinoid ligand. The 3-carboxyamide
group is seen in the arylpyrazoles and may play an important role in the binding of this compound. It
was noted that this compound displays anti-inflammatory effects in vivo.

A series of CB

selective 1,8-naphthyridines was synthesized after the development of 277

(

Ferrarini et al., 2004

). These compounds also have the 3-carboxyamide of the arylpyrazoles, but

contain an alkyl or arylalkyl substituent on the N1 position similar to that of the AAIs. These
compounds, shown in

Table 20

, display poor affinity for both receptors if there is no N1 substituent

(278, 279) or if there is a methylene spacer (304–309) between the ring system and the carboxyamide
group. The presence of an ethylmorpholino group as the N1 substituent conveys some affinity, but the

Table 19
Hydantoin derivatives (

Ooms et al., 2002

)

(CH

)nR

Number

Lipophilicity

267

N(CH

2)2

N/D

2.16

268

N(CH

2)2

N/D

3.49

269

N/D

7.04

270

N(CH

2)2

N/D

2.81

271

OCH

N(CH

2)2

N/D

2.73

272

N(CH

2)2

70.3 F 4.3

3.86

273

103.2 F 68

3.76

274

N/D

6.87

275

97.9 F 5.5

7.45

276

N/D

7.99

N/D = not determined; data from three independent experiments expressed as the mean of three values with standard error of

mean. Measured against [

H]SR141716 in CHO expressed human CB

Calculated using the CLIP method.

Fig. 6. JTE-907 (277).

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1792

presence of a benzyl or n-alkyl group results in a significant increase in affinity. Increased affinities
are observed if the carboxyamide group contains a cycloalkyl substituent over an aryl substituent. The
compound displaying the highest affinity for both receptors is 295, although better CB

selectivity is

Table 20
1,8-Naphthyridine derivatives (

Ferrarini et al., 2004

)

(CH

NHR

Number

(nM)

278

Cyclohexyl

1000

279

Benzyl

1000

280

ethylmorpholino

Cyclohexyl

1000

100 F 8

281

ethylmorpholino

Morpholino

1000

282

ethylmorpholino

cyclohexyl

1000

117 F 15

283

ethylmorpholino

N-CH

pipz

1000

284

ethylmorpholino

Benzyl

1000

475 F 25

285

ethylmorpholino

4-CH

-cyclohexyl

537 F 24

30 F 2

286

ethylmorpholino

Cyclopentyl

1000

50 F 4

287

ethylmorpholino

Cycloheptyl

560 F 33

22 F 2

288

ethylmorpholino

Isopentyl

1000

50 F 3

289

ethylmorpholino

p-Cl-Benzyl

1000

290

benzyl

Cyclohexyl

127 F 13

10 F 0.5

291

Benzyl

1000

292

Benzyl

p-Cl-Benzyl

1000

293

o-F-benzyl

Cyclohexyl

208 F 17

44 F 2

294

o-F-benzyl

Benzyl

1000

600 F 60

295

p-F-benzyl

Cyclohexyl

15 F 1.8

5.5 F 0.4

296

p-F-benzyl

Benzyl

457 F 40

65.3 F 6

297

n-hexyl

Cyclohexyl

95 F 3

8.0 F 0.2

298

n-hexyl

Benzyl

1000

325 F 25

299

n-butyl

Cyclohexyl

262 F 10.4

17.5 F 1

300

n-butyl

Benzyl

1000

301

ethylmorpholino

Benzyl

1000

302

ethylmorpholino

Cyclohexyl

1000

303

ethylmorpholino

Cyclohexyl

1000

25 F 1.8

304

ethylmorpholino

Benzyl

1000

305

Benzyl

1000

729 F 82

306

ethylmorpholino

Cyclohexyl

1000

307

Benzyl

Cyclohexyl

1000

530 F 50

308

n-hexyl

Cyclohexyl

1000

309

n-butyl

Cyclohexyl

1000

Affinity of compounds for CB

receptor was evaluated using mouse cerebellum membranes and [

H]-CP 55,940. Affinity

for CB

receptor was assayed using mouse spleen homogenate and [

H]-CP 55,940. K

values were obtained from five

independent experiments carried out in triplicate and are expressed as the mean standard error.

L.W. Padgett / Life Sciences 77 (2005) 1767–1798

1793

exhibited by several other compounds in this series. Decreased affinity is observed if the 7-methyl
group is replaced with an NH

group (301, 302), but replacement with Cl (303) gives a four-fold

increase in affinity for CB

Conclusion

The analogues produced in the last 2 years have filled gaps in the understanding of cannabinoid SAR

and posed many new questions. The pyrazoles are typically CB

selective, but the many of the analogues

shown in

Table 12

are highly CB

selective. Compound 174 is especially noteworthy since it is substituted

as SR141716, but is held rigid by the presence of a bridging methylene to form a cyclopentyl ring. This
opens up a new area of study for controlling receptor subtype specificity. As yet, there has been little
published in the way of CB

selective agonists, although there are CB

selective agonists in all the classes

discussed here. The indole and pyrrole series have many avenues left to be pursued regarding substitution
of the aryl systems and control of receptor selectivity. Particularly interesting would be an investigation of
derivatization of the naphthyl system of the pyrroles. The structure of the pyrroles is suggestive of the
pyrazoles; similar substitution patterns to the pyrazoles may prove fruitful on the pyrroles. It may be that
some of the pyrrole analogues emerge as antagonists or inverse agonists.

In summary, a significant number of exogenous ligands have been developed over the last 2 years,

largely focusing on developments in the pyrazole class. SR141716 is currently in clinical trials for
treatment of obesity, and this has fueled interest in the development of antagonists as therapeutic agents.
Repetition of previously observed themes is present in these compounds: benefits arising from lipophilic
groups up to a finite size, intramolecular hydrogen-bonding to establish low-energy conformations and the
availability of those conformations for binding. Also the effect of aromaticity on the cannabimimetic
effects of the AAI structural class has been investigated. Improved techniques in computational modeling
and pharmacological assays are providing more insight into directed ligand synthesis. There are many
questions yet to be answered concerning these structural classes and their abilities to not only interact with
the receptors but to generate biological activity that can be used therapeutically.

Acknowledgements

The author thanks Drs. John W. Huffman and Julia Brumaghim of Clemson University and Dr.

Clifford Padgett of North Carolina State University for helpful discussions concerning this review. The
work carried out at Clemson University included in this review was supported by Grants DA 03590, DA
03671, and DA 15579 from the National Institute on Drug abuse.

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