Discovery of 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif

Article abstract of DOI:10.1021/jm031099y

A new series of 1,2,4-triazoles have been prepared and the evaluation of their cannabinoid properties have been carried out. Compound 8 showed cannabinoid silent antagonist activity in mouse vas deferens and guinea pig ileum preparations and in vivo assay

Full text of DOI:10.1021/jm031099y

J . Med. Chem. 2004, 47, 2939-2942
2939
Discover y of 5-(4-Ch lor op h en yl)-1-(2,4-d ich lor op h en yl)-3-h exyl-1H-1,2,4-tr ia zole,
a Novel in Vivo Ca n n a bin oid An ta gon ist Con ta in in g a 1,2,4-Tr ia zole Motif
Nadine J agerovic,*,† Laura Hernandez-Folgado,† Ibon Alkorta,† Pilar Goya,† Miguel Navarro,# Antonia Serrano,‡
Fernando Rodriguez de Fonseca,‡ M. Teresa Dannert,| Angela Alsasua,| Margarita Suardiaz,§
David Pascual,§ and Maria Isabel Mart´ın§
Instituto de Qu´ımica Me´dica, Consejo Superior de Investigaciones Cient´ıficas, J uan de la Cierva, 3, E-28006 Madrid, Spain,
Departamento de Psicobiolog´ıa, Facultad de Psicolog´ıa, Universidad Complutense de Madrid, E-28040 Madrid, Spain,
Fundacio´n Hospital Carlos Haya, E-29010 Ma´laga, Spain, Facultad de Medicina, Universidad Complutense de Madrid,
E-28040 Madrid, Spain, and Unidad de Farmacolog´ıa, Facultad de Ciencias de la Salud, Universidad Rey J uan Carlos,
Avda. Atenas, s/ n, E-28922 Alcorco´n, Madrid, Spain
Received November 11, 2003
A new series of 1,2,4-triazoles have been prepared and the evaluation of their cannabinoid
properties have been carried out. Compound 8 showed cannabinoid silent antagonist activity
in mouse vas deferens and guinea pig ileum preparations and in vivo assays (cannabinoid
tetrad) in mouse. It did not have intrinsic activity in these bioassays, and therefore, it did not
behave as a partial agonist or an inverse agonist.
Sch em e 1a
In tr od u ction
Recognition and evidence of at least two types of
cannabinoid receptors CB1 and CB2 and the discovery
of endogenous cannabinoid ligands have prompted the
research of novel cannabinoid receptor agonists and
antagonists.1-3 A wide range of CB1 and CB2 ligands
with diverse chemical structures are now available.4,5
We report a silent cannabinoid antagonist derived from
a 1,2,4-triazole that represents a novel entry in can-
nabinoid chemistry.6 Although diverse heterocyclic struc-
tures such as the pyrazoles SR141716 and SR1445287,8
or the aminoalkylindole AM6309 or, more recently,
imidazolinediones10 have been shown to be cannabinoid
receptor antagonists, triazoles have not yet been ex-
plored within this context. Thus, we describe the
synthesis of a series of 1,2,4-triazoles, their in vitro and
in vivo evaluation, and the identification of 8 as a silent
antagonist.
a
Reagents and conditions: (a) (Me(CH2)n(CO)2O, dry toluene,
concentrated H2SO4, reflux; (b) phenylhydrazine for 5 and 10;
4-chlorophenylhydrazine for 6 and 7; 2,4-dichlorophenylhydrazine
for 8 and 9; AcOH, NaOAc, reflux.
for cannabinoid receptors was determined in rat cer-
ebellar membranes. Finally, they were tested in vivo
using the classic cannabinoid tetrad of behavioral tests.
2.1. Isola ted Tissu es Assa ys. The mouse vas def-
erens and the myenteric plexus-longitudinal muscle
(MP-LM) strips of guinea pig ileum are two isolated
tissues widely used to easily characterize cannabinoid
agonists and antagonists.12 In guinea pig ileum the
cannabinoid agonists acting at prejunctional cannab-
inoid receptors reduce acetylcholine release13 and inhibit
the electrically evoked contractions. This effect is ac-
cepted to be mediated through CB1 receptors,14 and the
inhibition is selectively reversed by the CB1 cannabinoid
antagonist SR141716. Inhibition of the electrically
induced contractions by cannabinoid agonists have also
Resu lts a n d Discu ssion
1. Ch em istr y. Triazoles 5-10 were prepared from
the corresponding N-acylbenzamides 1-4 as described
in Scheme 1.11 These N-acylbenzamides 1-4 were
obtained by treatment of benzamides with anhydrides
in toluene in the presence of concentrated H2SO4. Then
condensation with the corresponding phenylhydrazines
in acetic acid led to triazoles 5-10.
2. P h a r m a cology. To evaluate the biological activity
of the new compounds 5-10, three sets of experiments
were carried out. First, their effect in isolated tissues
in order to determine whether they behave as cannab-
inoid agonists or antagonists was tested. Then for those
compounds showing interesting profiles, their affinity
15
been described in mouse vas deferens. CB1 and CB2-
* To whom correspondence should be addressed. Phone: (34) 91 561
8806. Fax: (34) 91 564 4853. E-mail: nadine@iqm.csic.es.
† Consejo Superior de Investigaciones Cient´ıficas.
like16 cannabinoid receptors seem to be involved in this
effect.
#
Facultad de Psicobiolog´ıa, Universidad Complutense de Madrid.
As an expected cannabinoid agonist used as a refer-
ence compound, WIN 55,212-2 was able to induce dose-
dependent inhibition of the electrically induced contrac-
‡ Fundacio´n Hospital Carlos Haya.
| Facultad de Medicina, Universidad Complutense de Madrid.
§ Universidad Rey J uan Carlos.
10.1021/jm031099y CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004

2940 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11
Brief Articles
F igu r e 1. Lines show the mean % (n ) 7) of modification of
the electrically induced contraction of the mouse vas deferens
by cumulative addition of WIN 55,212-2 (WIN) or the new
compounds. SEM was not included in the figure to clarify the
presentation (table in Supporting Information).
tions in mouse vas deferens and in guinea pig ileum.
This effect was also dose-dependently antagonized by
the CB1 cannabinoid antagonist SR141716. When the
effect of 5-10 was tested, they did not induce significant
modification of the contractile responses in the mouse
vas deferens (10-8-10-6 M) (see Figure 1). Similar
results were found when their effect was tested in the
guinea pig ileum (10-8 to 2.4 × 10-6 M). These data
eliminate the possibility that the new compounds act
as cannabinoid agonists. It could also be established that
they lack both direct (activation) or indirect (induction
of the neurotransmitter release) agonist activity on a
large number of well-known receptors that play a role
in the electrically induced contraction in mouse vas
deferens (adrenergic, purinergic, cannabinoid, δ, µ, and
κ opioid receptors) or in guinea pig ileum (cholinergic,
histaminergic, serotonergic, adrenergic, susbstance P,
µ and κ opioids, cannabinoid, CGRP, VIP, purinergic
receptors). Compound 5 induced inhibition of the con-
tractile activity in the guinea pig ileum. This effect was
not antagonized by SR141716 disregarding cannabinoid
agonistic activity, and more studies are required to
determine the mechanism underlying this inhibition. No
statistical differences were found between tissues in-
cubated with 6-10 and control or vehicle-treated tissues
(see Supporting Information). To evaluate if 5-10 can
act as cannabinoid antagonists, the effect of WIN 55,-
212-2 was tested in tissues incubated with the triazoles.
Compound 8 induced a significant and dose-dependent
decrease of the inhibition evoked by cannabinoid ago-
nists in both tissues. Figure 2 shows the inhibition of
the WIN effect induced by SR141716 and 8 in mouse
vas deferens. From these data, it could be suggested that
8 is a cannabinoid antagonist lacking agonistic activity.
2.2. Bin d in g Assa y. Radioligand displacement as-
says have been used to evaluate the affinity of 8 to CB1
receptors in rat cerebellar membranes. They have been
performed with [3H]-SR141716A and [3H]-WIN 55,212-2
as labeled ligands. Compound 8 retained a moderate
affinity (Ki ) 855.6 ( 296 nM and Ki ) 748 ( 193 nM,
respectively) for CB1 receptors. Although 8 was shown
in our functional studies to have antagonistic efficacy
in vitro and in vivo similar to that of SR141716A, it has
a reduced affinity for CB1 receptors compared to
SR141716 (Ki ) 4 nM).
F igu r e 2. Lines show the mean % ( SEM (n ) 7) of
modification of the electrically induced contraction of the
mouse vas deferens by cumulative addition of WIN 55,212-2
(WIN) in control tissues or in tissues incubated with SR141716A
(SR) in the top panel or of 8 in the bottom panel. The asterisk
represents the significant difference vs control tissues: (/) p
< 0.05; (///) p < 0.001.
ties and biological activities have been described for
many compounds including dopamine uptake blockers17
and cannabinoids.18 They might be dependent on the
nature of receptor-ligand interaction (competitive and
noncompetitive antagonism), type of in vitro assay
(cations, presence of GDP/GTP analogues), existence of
receptor subtypes including constitutively active recep-
tors (described also for CB1 receptors),19 or local cellular
G-protein concentration. Additionally, inverse agonists
bind preferentially to normal receptors with higher
affinity than neutral antagonists.20
2.3. Ca n n a bin oid Tetr a d of Beh a vior a l Tests. The
effect of 8 was tested using a well accepted model to
evaluate cannabinoid compounds in vivo: the cannab-
inoid tetrad. Treatment with 8 did not induce significant
modifications in any of the tested parameters (nocice-
ption, temperature, spontaneous motility, and cata-
lepsy), discarding again agonistic activity, whereas the
cannabinoid agonist WIN 55,212-2 induced dose-de-
pendent antinociception, hypothermia, inhibition of
spontaneous motility, and catalepsy. Figure 3 shows the
effect of the intraperitoneally (ip) administration of 1.5
mg/kg of WIN 55,212-2 in control animals and after the
ip administration of 1 mg/kg of 8 or of reference
antagonist SR141716. These data are in agreement with
Binding results do not corroborate the results ob-
tained in isolated tissues. Differences in binding affini-

Brief Articles
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11 2941
in particular for antagonistic properties. However, tria-
zole 8 showed a moderate affinity for CB1 receptors. To
get insight on this discrepancy, on a first approximation,
a superposition of the 1,2,4-triazole structure with a
common pharmacophore for cannabinoid ligands that
was constructed whatever their structure and their
activity (agonist, antagonist, or inverse agonist) was
attempted. For the modeling of the pharmacophore, the
classical cannabinoids ∆9-THC, nabilone, and cannab-
inol, pyrazole SR141716, aminoalkylindole J WH018,
and aminoalkylpyrrole J WH030, all described in the
literature,1,4 were selected. The alignment of our triazole
series with the selected molecules and the template ∆9-
tetrahydrocannabinolic acid B (thcanb)22 agreed with
the following elements involved in the pharmacophore:
hydrocarbon area, aromatic ring, heteroatom, and ali-
phatic chain (see Supporting Information).
In summary, we have identified 1,2,4-triazole as a
new heterocyclic core with potential cannabinoid prop-
erties. In particular 8 behaves as a CB1 antagonist both
in vivo and in functional assays. However, the affinity
of 8 for rat cerebellar CB1 receptors was revealed to be
moderate. Although further investigations are now
required to establish the mechanism and interactions
that contribute to its in vitro and in vivo pharmacologi-
cal effects, triazole 8 can be considered as a lead in the
search for silent cannabinoid receptor antagonists.
Exp er im en ta l Section
Ch em istr y. Gen er a l P r oced u r e for P r ep a r in g N-Acyl-
a m id es 1-4. The preparation of N-heptanoyl-4-chlorobenz-
amide (2) is given as a representative example.
N-Hep ta n oyl-4-ch lor oben za m id e (2). To a suspension of
4-chlorobenzamide (3.89 g, 25.0 mmol) in dry toluene (40 mL)
was added heptanoic anhydride (10.5 mL, 40.0 mmol) and
concentrated H2SO4 (0.5 mL). The reaction mixture was heated
to reflux for 1 h. The resulting dark solution was treated with
activated carbon and filtered over Celite. The solvent was
evaporated under reduced pressure, and the residue was
washed with water. Recrystallization from EtOH gave 2.70 g
of 2 (40%) as a white solid: mp 139-142 °C; MS (ES+) m/z
(rel intensity %) 268 (M+ + 1, 100). Anal. (C14H18ClNO2) C, H,
N.
N-P r op a n oyl-4-ch lor oben za m id e (1) was prepared from
4-chlorobenzamide (1.00 g, 6.4 mmol) and propionic anhydride
(1.32 mL, 10.3 mmol) as described for 2: yield, 451 mg (33%)
as a white solid; mp 141-145 °C (lit.11 163-165 °C); MS (ES+)
m/z (rel intensity %) 212 (M+ + 1, 95). Anal. (C10H10ClNO2) C,
H, N.
N-Hep ta n oyl-2,4-d ich lor oben za m id e (3) was prepared
from 2,4-dichlorobenzamide (4.75 g, 25.0 mmol) and heptanoic
anhydride (10.5 mL, 40.0 mmol) as described for 2: yield, 4.18
g (55%) as a white solid; mp 65-69 °C; MS (ES+) m/z (rel
intensity %) 302 (M+ + 1, 100). Anal. (C14H17Cl2NO2) C, H, N.
N-Octa n oylben za m id e (4). White solid; mp 62-64 °C; MS
(ES+) m/z (rel intensity %) 248 (M+ + 1, 90). Anal. (C14H17Cl2-
NO2) C, H, N.
Gen er a l P r oced u r e for P r ep a r in g 3-Alk yl-1,5-d ia r yl-
1H-1,2,4-tr ia zoles 5-10. The preparation of 5-(4-chloro-
phenyl)-3-ethyl-1-phenyl-1H-1,2,4-triazole (5) is given as a
representative example.
5-(4-Ch lor op h e n yl)-3-e t h yl-1-p h e n yl-1H -1,2,4-t r ia -
zole (5). Phenylhydrazine (0.24 mL, 1.4 mmol) and NaOAc
(153 mg, 1.9 mmol) were added to a solution of 1 (300 mg, 1.4
mmol) dissolved in glacial acetic acid (10 mL). The reaction
mixture was heated to reflux for 22 h. The solvent was
evaporated. The residue was then dissolved in CH2Cl2 and
washed with H2O. The organic layer was then dried over
MgSO4, and the solvent was evaporated. The orange residue
was purified on flash chromatography (EtOAc/n-hexane 1:2
F igu r e 3. Effects on the cannabinoid tetrad. Bars show
modifications induced by treatment with WIN 55,212-2 (WIN),
8, and WIN after treatment with SR141716A (SR) or 8. Values
show the mean ( SEM (n ) 10). The asterisk represents the
significant difference vs control value: (/) p < 0.05; (//) p <
0.01; (///) p < 0.001). The # represents significant difference
vs WIN bar: (#) p < 0.05; (##) p < 0.01; (###) p < 0.001.
those recorded in mouse vas deferens and in guinea pig
ileum, and although more experiments are required to
better characterize this compound, it can be suggested
that 8 behaves as a CB1 cannabinoid antagonist.
3. Molecu la r Mod elin g. Extensive SAR studies have
yielded information on structural requirements for
cannabinoid receptor affinity, and pharmacophores for
the major classes of cannabinoid ligands have been
reported.21 The 1,2,4-triazoles series reported here
constitute a new template for cannabinoid activity and

2942 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11
Brief Articles
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to 2:1) to give 5 as a yellowish solid (10%): mp 76-79 °C; MS
(ES+) m/z (rel intensity %) 284 (M+ + 1, 100). Anal.
(C16H14ClN3) C, H, N.
1,5-Bis(4-ch lor oph en yl)-3-eth yl-1H-1,2,4-tr iazole (6) was
prepared from 1 (300 mg, 1.4 mmol), 4-chlorophenylhydrazine
(202 mg, 1.4 mmol), and NaOAc (153 mg, 1.9 mmol) as
described for 5 (chromatography, CH2Cl2/n-hexane 1:1 to
1:0): yield, 29 mg (6%) as a brownish solid; mp 94-96 °C (lit.11
94-95 °C); MS (ES+) m/z (rel intensity %) 318 (M+ + 1, 100).
Anal. (C16H13Cl2N3‚2.5H2O): C, calcd, 52.90; found, 52.60. H,
calcd, 4.99; found, 4.19. N, calcd, 11.57; found, 10.99.
1,5-Bis(4-ch lor oph en yl)-3-h exyl-1H-1,2,4-tr iazole (7) was
prepared from 2 (700 mg, 2.6 mmol), 4-chlorophenylhydrazine
(544 mg, 3.8 mmol), and NaOAc (284 mg, 3.5 mmol) as
described for 5 (chromatography, EtOAc/n-hexane 1:7 to 1:1):
yield, 113 mg (12%) as a yellow oil; MS (ES+) m/z (rel intensity
%) 374 (M+ + 1, 100). Anal. (C20H21Cl2N3) C, H, N.
5-(4-Ch lor op h en yl)-1-(2,4-d ich lor op h en yl)-3-h exyl-1H-
1,2,4-tr ia zole (8) was prepared from 2 (700 mg, 2.6 mmol),
2,4-dichlorophenylhydrazine (442 mg, 2.6 mmol), and NaOAc
(284 mg, 3.5 mmol) as described for 5 (chromatography,
CH2Cl2/n-hexane 1:1 to 2:1): yield, 94 mg (9%) as a white solid;
mp 60-63 °C; MS (ES+) m/z (rel intensity %) 408 (M+ + 1,
76). Anal. (C20H20Cl3N3) C, H, N.
1,5-Bis(2,4-dich lor oph en yl)-3-h exyl-1H-1,2,4-tr iazole (9)
was prepared from 3 (1.0 g, 3.3 mmol), 2,4-dichlorophenyl-
hydrazine (595 mg, 3.5 mmol), and NaOAc (433 mg, 5.3 mmol)
as described for 5 (chromatography, EtOAc/n-hexane 1:9 to
1:1): yield, 84 mg (6%) as a yellow oil; MS (ES+) m/z (rel
intensity %) 442 (M+ + 1, 78). Anal. (C20H19Cl4N3) C, H, N.
1,5-Dip h en yl-3-h ep tyl-1H-1,2,4-tr ia zole (10) was pre-
pared from 4 (100 mg, 0.4 mmol), phenylhydrazine (44 mg,
0.4 mmol), and NaOAc (44 mg, 0.5 mmol) as described for 5
(chromatography, CH2Cl2/n-hexane 8:2, CH2Cl2/MeOH 9:1):
yield, 13 mg (10%) as a yellow oil; MS (ES+) m/z (rel intensity
%) 320 (M+ + 1, 100).
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Ack n ow led gm en t. This work was supported by
Spanish Grant SAF 00-0114-C02. L.H.-F. is recipient
of the I3P Fellowship from the C.S.I.C. Laboratorios Dr.
Esteve, S.A. is gratefully acknowledged. L.H.-F. thanks
the Spanish Society of Therapeutic Chemistry (SEQT)
for the Ramon Madron˜ero Young Researcher Award.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
data and assignments for 1-10, CHN analysis, experimental
details with references and a figure from molecular modeling,
protocols of biological assays in isolated tissues, data of the
guinea pig ileum assays, statistical analysis, protocols of
cannabinoid tetrad in vivo, and binding tests. This material
is available free of charge via the Internet at http://
pubs.acs.org.
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J M031099Y