[1,2,4]Triazole derivatives as 5-HT1A serotonin receptor ligands

Article abstract of DOI:10.1016/S0968-0896(01)00281-4

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT_1A receptor over the α₁-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT_1A receptor and α₁-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT_1A receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole3-3-thiones 12a-r preferentially bind to the α₁-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT_1A receptor (K_iα₁/K_i5-HT_1A=55). The decrease in 5-HT_1A=55). The decrease in 5-HT_1A = 55). The decrease in 5-HT_1A receptor selectivity in 3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl) [1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in derermining 5-HT_1A receptor selectivity in this class of compounds. Copyright

Full text of DOI:10.1016/S0968-0896(01)00281-4

Bioorganic & Medicinal Chemistry 10 (2002) 313–323
[1,2,4]Triazole Derivatives as 5-HT1A Serotonin Receptor Ligands
Maria Concetta Sarva,a Giuseppe Romeo,a Francesco Guerrera,a Mariangela Siracusa,a
Loredana Salerno,a Filippo Russo,a,* Alfredo Cagnotto,b Mara Goeganb
and Tiziana Menninib
a
`
Dipartimento di Scienze Farmaceutiche, Universita di Catania, viale A. Doria 6, 95125 Catania, Italy
bIstituto di Ricerche Farmacologiche ‘‘Mario Negri’’, via Eritrea 62, 20157 Milan, Italy
Received 2 March 2001; accepted 1 August 2001
Abstract—A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles
11a–t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT1A receptor over the a1-adrenoceptor. A
series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-
3H[1,2,4]triazole-3-thiones 12a–r was also isolated and characterized. New compounds were tested to evaluate their affinity for
5-HT1A receptor and a1-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a–t showed a preferential
affinity for the 5-HT1A receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a–r preferentially bind to the a1-adre-
noceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piper-
azinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT1A receptor (Ki a1/Ki
5-HT1A=55). The decrease in 5-HT1A receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(sub-
stitutedphenyl)[1,2,4] triazole 14a–b, lacking in the amino group in 4-position of the triazole ring, in comparison with their ana-
logues in the series 11a–t, suggest that the amino function represents a critical structural feature in determining 5-HT1A receptor
selectivity in this class of compounds. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
be subdivided into different classes.8,9 Some effective
5-HT1A receptor partial agonists such as buspirone 2
and ipsapirone 3 belong to the arylpiperazine class and
they are currently used in therapy as anxiolitic and
antidepressant drugs. However, a limitation in the
potential use of many 5-HT1A receptor ligands as drugs
or pharmacological tools, is their undesired high affinity
for other receptor subtypes. The dopaminergic D2
receptor and the a1-adrenoceptor are two examples of
receptor sites to which several 5-HT1A ligands bind with
high affinity. For example, possibly as a reflection of
the high degree of similarity (45%) in the amino acid
sequence between the 5-HT1A and the a1-adrenoceptor,
some 5-HT1A receptor ligands such as NAN190 4 show
good affinity for the a1-adrenoceptor sites.10,11 On the
other hand, some well-known a1-adrenoceptor ligands,
such as WB4101 5 or BMY 7378 6, bind to 5-HT1A
receptor.12ꢀ14
Serotonin (5-HT) is an important neurotransmitter that
mediates a wide variety of physiological responses in
both the peripheral and central nervous systems.
The receptors activated by 5-HT have been divided into
at least seven classes (5-HT1ꢀ7) and each class has been
further subdivided into different subtypes.1 Among
them, the 5-HT1A receptor is one of the best studied, as a
result of the early availability of selective ligands such as
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)
1 (Chart 1) which in the tritiated form is used to label
the 5-HT1A receptor and whose R enantiomer acts as a
potent 5-HT1A agonist.2 The 5-HT1A receptor has been
cloned and belongs to the G-protein coupled receptors
superfamily.3 It is generally accepted that it is involved in
psychiatric disorders such as depression and anxiety.4ꢀ6 In a
recent paper, 5-HT1A-knockout mice were shown to behave
with an anxiety-related disorder similarly to humans.7
In the last years, many efforts have been made to discover
5-HT1A receptor ligands devoid of affinity for a1-adreno-
ceptor.11,15,16 In previous papers we have reported the
synthesis of new thieno[2,3-d]pyrimidines as 5-HT1A
receptor ligands.17,18 Some of them, such as compound
7 and its nitro derivative 8 had shown high affinity at
the 5-HT1A receptor sites coupled to a reduced a1-adre-
Several potent 5-HT1A receptor ligands are already
known and, from a chemical point of view, they can
*Corresponding author. Tel.: +39-095-330836; fax: +39-095-222239;
e-mail: gromeo@mbox.unict.it
0968-0896/02/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00281-4

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
314
Chart 1.
nergic affinity. As in many arylpiperazine ligands, the
structures of 7 and 8 can be subdivided in three princi-
pal parts. One is represented by the phenylpiperazinyl
(PP) moiety, which forms an essential part of the phar-
macophore of the molecule for 5-HT1A affinity. The
second is constituted by a thioalkyl chain (whose length
highly influences affinity and selectivity for the 5-HT1A
receptor) which connects the PP moiety with the third
part, the 3-amino-5,6-dimethylthieno[2,3-d]pyrimidine-
4(3H)-one heterocycle. Several structural modifications
have already been made in this heterocyclic moiety by
changing the nature of substituents or by substitution of
the thiophene ring for other heterocyclic rings.17,18
From these studies, the presence of an amino group in
3-position of the thieno[2,3-d]pirimidine nucleus
emerged as one of the most important structural fea-
tures which, in this class of molecules, induces high
affinity and selectivity for the 5-HT1A receptor.
new series, an N-amino substituent is mantained in the
ortho position respect to the thioalkyl chain. Sub-
stituents on the phenyl ring in the 5-position of triazole
ring were chosen with the aim of varying the physico-
chemical properties. They were selected according to the
principal properties approach, in which the original
variables (p, MR, sm, sp, Sterimol parameters: L and
Bi–Biv) for each substituent are described by means of
fewer new variables which are linear combinations of the
original ones and are mutually uncorrelated.19 Thus, we
selected the following eight substituents: CH3O, CH3, Cl,
Br, n-C3H7O, C6H5SO2, C6H5OCH2 and C6H5, in the
para position of the phenyl ring. We also decided to
enlarge the series with the preparation of some meta or
ortho substituted and unsubstituted derivatives.
During the synthesis of the new compounds, we noticed
that, together with the desired triazole (11a–t), isomeric
2,4-dihydro-3H[1,2,4]triazole-3-thione derivatives (12a–r)
(Table 1) were also formed. In many cases, we also accom-
plished their isolation and structural characterization.
With the aim to obtain new 5-HT1A receptor ligands
with improved selectivity over the a1-adrenoceptor, we
now report a new series of derivatives 11a–t, structurally
related to compounds 7 and 8, in which the 3-amino-
5,6-dimethylthieno[2,3-d]pyrimidine-4(3H)-one part was
exchanged for a 4-amino-5-aryl[1,2,4] triazole. In this
We also synthesized compound 11u, along with its iso-
mer 12s, bearing a shorter connecting chain between the
PP moiety and the triazole ring.

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
315
To test the importance of the N-amino group for the
interaction of new compounds with the 5-HT1A recep-
tor, we prepared analogues 14a–b (Table 1) lacking in
the amino function in 4-position of triazole ring.
in many cases, we were able to isolate these side pro-
1
ducts. Analysis of the H NMR spectra of the two iso-
meric series is diagnostic for the assignment of
structure. Both spectra present, in the range from 5.8 to
6.2 d, a broad singlet signal which integrates for two
hydrogens and disappeares in presence of D2O; it is
Compounds 11a–u and 14a–b along with some 2,4-
dihydro-3H[1,2,4]triazole-3-thione derivatives (12a–e,
12g, 12s) were tested in binding experiments to evaluate
their affinity and selectivity for the 5-HT1A receptor
with respect to the a1-adrenoceptor.
1
analogous to the signal seen in the H NMR spectra of
4-amino-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]tri-
azole-3-thiones (9a–k) and it has to be attributed to the
NH2 group. This implies that alkylation of compounds
9a–k does not take place at the NH2 substituent. In
both spectra, a triplet for the methylene group of the
propyl chain that connects the PP moiety and the tria-
zole part of the molecule, is observed. For derivatives
11a–u, this triplet has a chemical shift of 3.15 d, which is
typical for S–CH2 connectivity, and for isomers 12a–s of
4.2 d, which is typical for N–CH2 connectivity.18
Chemistry
The general strategy for the synthesis of compounds
11a–u and 12a–s is summarized in Scheme 1. A number
of 4-amino - 5 - (substitutedphenyl) - 2,4 - dihydro -
3H[1,2,4]triazole-3-thiones (9a–k) were chosen as start-
ing materials. They were reacted in ethanol, in the pre-
sence of sodium hydroxide and a catalytic amount of
potassium iodide, with 1-(3-chloropropyl)-4-(2-methox-
yphenyl)piperazine (10a), 1-(3-chloropropyl)-4-(2-nitro-
phenyl)piperazine (10b) or 1-(2-chloroethyl)-4-(2-
methoxyphenyl)piperazine (10c), to give desired pro-
ducts 11a–u (Table 1) in moderate to good yields. In
these experimental conditions, isomeric N-alkylated
derivatives 12a–s were also formed in lower yields and,
Many of the starting 4-amino-5-(substitutedphenyl)-2,4-
dihydro-3H[1,2,4]triazole-3-thione were already known
(compounds 9a–c, 9f–g) and were prepared as previous
described.20ꢀ22 The synthesis of starting materials 9d
and 9h–k was accomplished following the procedure
described in Scheme 2. The appropriate benzoylhydrazide
was reacted with carbon disulfide in presence of potas-
sium hydroxide to give the corresponding potassium
dithiocarbazinate which in presence of hydrazine hydrate
afforded 4-amino-5-(substitutedphenyl)-2,4-dihydro-
3H[1,2,4] triazole-3-thiones (9d, 9h–k) in good yields.
Table 1. Structure of compounds 11a–u, 12a–s and 14a–b
The preparation of derivatives 14a and 14b (Table 1),
which lack the amino substituent in the 4-position of the
triazole, was accomplished using similar reaction condi-
tions as for the synthesis of compounds 11a–u. 5-Phenyl-
2,4-dihydro-3H[1,2,4]triazole-3-thione (13a) or 5-(4-
methoxyphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thione
(13b) and 1-(3-chloropropyl)-4-(2-methoxyphenyl)piper-
azine (10a) are reacted in alcaline medium (Scheme 3).
In this case, only the S-alkylated isomers 14a–b were
isolated from the reaction mixture.
Pharmacology
Compound
n
R
X
The affinity of test compounds 11a–s, 12a–e, 12g, 12s,
6a and 6b for 5-HT1A and a1 receptors was established
by measuring their ability to displace in vitro the radio-
ligands [3H]-8-OH-DPAT (rat hippocampus) or [3H]-
prazosin (rat cortex), respectively. Compounds 11h, 11i
and 11o were also tested in binding assays to evaluate
their affinity for the dopaminergic D2 receptor using
[3H]spiperone (rat striatum) as radioligand. The results
are summarized in Table 2and expressed as Ki (nM)
values along with the affinities of buspirone 2 and ipsa-
pirone 3 for comparison.23
11a, 12a, 14a
11b, 12b
11c, 12c
11d, 12d
11e, 12e, 14b
11f, 12f
11g, 12g
11h, 12h
11i, 12i
11j, 12j
11k, 12k
11l, 12l
11m, 12m
11n, 12n
11o, 12o
11p, 12p
11q, 12q
11r, 12r
11s
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
H
H
2-Cl
2-Cl
4-CH3O
4-CH3O
3-CH3O
3-CH3O
4-CH3
4-CH3
4-Cl
4-Cl
4-Br
CH3O
NO2
CH3O
NO2
CH3O
NO2
CH3O
NO2
CH3O
NO2
CH3O
NO2
CH3O
NO2
CH3O
NO2
4-Br
4-n-C3H7O
4-n-C3H7O
4-C6H5SO2
4-C6H5SO2
4-C6H5OCH2
4-C6H5
4-n-C3H7O
Results and Discussion
CH3O
NO2
CH3O
CH3O
CH3O
As a general trend, compounds 11a–t, with the phe-
nylpiperazinylpropyl chain bonded to the exocyclic sul-
fur atom, showed good and preferential affinity for the
5-HT1A receptor over the a1-adrenoceptor whereas most
11t
11u, 12s

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
316
Scheme 1. Synthesis of compounds 11a–u and 12a–s. Reagent and conditions: (i) EtOH, KOH, reflux.
11-series, they also showed a higher 5-HT1A selectivity
as compared to the nitro analogues. It should be noted,
however, that the nitro analogue 11h (Ki 5-HT1A
=3.69 nM) shows a higher selectivity than its methoxy
analogue 11g (ratio 43 vs 21).
In general, in the 11-series, substituents on the phenyl
ring in the 5-position of the triazole seem to have little
effect on 5-HT1A receptor affinity. All the 2-methoxy-
phenylpiperazinyl compounds showed good affinity for
the receptor with variations in Ki values not greater
than one order of magnitude (1.71ꢁKiꢁ12.86), with
11c having the highest affinity.
Scheme 2. Synthesis of compounds 9d, 9h–k. Reagent and conditions:
(i) CS2, KOH, EtOH, reflux; (ii) N2H4, reflux.
of compounds 12a–e, 12g, bearing the phenylpiper-
azinylpropyl chain in 2-position of the 2,4-dihydro-
3H[1,2,4]triazole-3-thione ring, displayed a preferential
affinity for the a1-adrenoceptor. Besides the obvious
differences in connectivity, the two series of molecules
differ in the length of the connecting chain between the
triazole and the piperazine ring. In compounds 11a–t,
the spacer is four atoms long whereas in 12a–e and 12g
it is one atom shorter. In previous series of arylpiper-
azine 5-HT1A receptor ligands, the optimum chain
length for 5-HT1A receptor affinity appeared to be four
atoms.17,24,25 A decrease in length of the chain often
increase a1-adrenoceptor affinity. This might explain the
observed differences in affinity/selectivity between com-
pounds 11a–t, 12a–e and 12g.
Compounds such as 11i, bearing a 4-methyl group, and
11s with a bulkier 4-phenoxymethyl substituent display
similar affinity values for the 5-HT1A receptor (11i,
Ki=1.77 nM; 11s, Ki=1.71 nM). Since the initial selec-
tion of substituents had been done trying to maximize
variations in their physical–chemical features, the
observed trend suggests that the receptor binding site is
able to accomodate substituents of different nature and
shape. On the other hand, introduction of a substituent
on the phenyl ring generally leads to an increase in 5-
HT1A receptor selectivity, with the exceptions of com-
pounds 11q and 11r (R=4-C6H5SO2). Compound 11o
(R=4-C3H7O) shows the highest selectivity in this series
(ratio of 55).
In general, the 2-methoxyphenylpiperazinyl derivatives
showed higher affinity at both receptor sites than their
respective 2-nitrophenylpiperazinyl analogues. In the
The 5-HT1A receptor affinity of 2,4-dihydro-3H[1,2,4]tri-
azole-3-thione derivatives (12a–e, 12g), having a shorter
connecting chain, was notably lower than the affinity

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
317
Scheme 3. Synthesis of compounds 14a–b. Reagent and conditions: (i) EtOH, KOH, reflux.
showed by their structural isomers 11a–e and 11g.
However, with the exception of compound 12c, they
showed increased affinity for the a1-adrenoceptor sites.
As a result of these two trends, 5-HT1A selectivity is lost
and, with the exception of compound 12e, a modest a1-
adrenoceptor selectivity is obtained.
Table 2. In vitro affinities of test compounds 11a–u, 12a–e, 12g, 12s
and 14a–b at the 5-HT1A a1 and D2 receptors sites (Ki in nMꢂSD)a
Compound
5-HT1A
a1
D2
Selectivityb
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
11r
11s
11t
11u
12a
12b
12c
12d
12e
12g
12s
14a
14b
2
2.68ꢂ0.13
23.05ꢂ2.99
1.03ꢂ0.1
16.30ꢂ2.92
95.25ꢂ18
15.51ꢂ2.18
78.70ꢂ17
ꢂ1.39
NTc
NT
NT
NT
NT
NT
NT
6
4
15
10
18
14
In compound 11u, the connecting thioalkyl chain is one
methylene shorter than in 11o. Although 11u showed
lower affinity for both 5-HT1A and a1 receptors, the
decrease was more evident at the 5-HT1A sites. This
resulted in a 10-fold loss of selectivity with respect to
11o. Compound 12s, the regioisomer of 11u, displayed
the lower 5-HT1A receptor affinity among test com-
pounds and, as the other derivatives in the 12-series, a
modest a1-adrenoceptor selectivity.
7.66ꢂ0.99
3.84ꢂ0.3269.33
17.80ꢂ3.18
2.3ꢂ0.79
258.3ꢂ19
47.84ꢂ5.10
21
3.69ꢂ0.83
1.77ꢂ0.43
29.56ꢂ7
167.349ꢂ0322
70.96ꢂ13
ꢂ40
43 (78)d
40 (72)d
9
127ꢂ15
NT
NT
262.59ꢂ9.43
77.38ꢂ5.87
211.34ꢂ14.71
91.21ꢂ5.48
132.21ꢂ14.15
2.84ꢂ0.27
21.91ꢂ3.28
2.96ꢂ0.27
27.35ꢂ2.19
2.85ꢂ0.18
26.74ꢂ0.76
27
10
31
5
NT
NT
NT
157.49ꢂ67.40 136ꢂ27
55 (48)d
10
Compounds 14a and 14b, analogues of 11a and 11e,
respectively, lack the NH2 group in 4-position on the
triazole ring and were synthesized and tested to evaluate
the importance of the amino function in the formation
of the receptor-ligand complex. As previously reported,
the amino group present in the structure of thieno[2,3-
d]pyrimidines 7 and 8 improves their 5-HT1A receptor
selectivity by enhancing the affinity of the molecules for
this receptor over the a1-adrenoceptor.18
276.11ꢂ58.54
ꢂ5.69
NT
NT
NT
NT
12.86ꢂ0.8243.76
3
1.4
15
114.37ꢂ12.81 168.24ꢂ21.76
1.71ꢂ0.11
4.18ꢂ0.29
48.8ꢂ3.0
54ꢂ5
24.9ꢂ4
134.3ꢂ2
274.4ꢂ44.3
17ꢂ1
7
NT
5.6
0.3
32
NT
NT
NT
NT
NT
NT
NT
NT
314ꢂ54
77ꢂ5
43ꢂ5
0.1
0.5
0.2
1.8
0.8
0.3
39ꢂ5
188ꢂ15
10ꢂ1
40ꢂ3
18ꢂ4
14ꢂ1
12ꢂ1
Compounds 14a and 14b were equipotent in 5-HT1A
affinity to compounds 11a and 11e. However, the affi-
nity for the a1-adrenoceptor site has increased 10-fold.
As a consequence, compounds 14a and 14b do not show
any 5-HT1A/a1 receptor selectivity. Thus, in this 1,2,4-
triazole class, the NH2 substituent enhances selectivity
via its detrimental effect on a1-adrenoceptor affinity.
461ꢂ38.2147.3
1.85ꢂ0.30
2.50ꢂ0.20
15e
ꢂ16.6
1.71ꢂ0.42NT
6.13ꢂ0.25
600e
0.9
NT
42e
400e
2.4
40 (2.8)d
36 (72)d
3
5.5e
200e
aKi values were calculated as described in Experimental and are means
(ꢂSD) of three separate experiments.
bSelectivity for 5-HT1A over a1 receptor is expressed as the ratio Ki
a1/Ki 5-HT1A
.
Compounds 11h, 11i and 11o, the most selective deriva-
tives for the 5-HT1A over the a1 receptor, were also tes-
ted in binding assays to evaluate their affinity for the
dopaminergic D2 receptor. They proved to be poor D2
cNT, not tested.
dSelectivity for 5-HT1A over D2 receptor is expressed as the ratio Ki
D2/Ki 5-HT1A
eData taken from ref 23.
.

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
318
ligands; their D2/5-HT1A selectivity ratios are compar-
able to the ratio showed by ipsapirone and notably
higher than the one of buspirone.
resulting mixture was stirred overnight. The solid potas-
sium dithiocarbazinate was filtered off, washed with ether
and dried (2.38 g). It was then dissolved in water (5 mL)
and hydrazine monohydrate (0.771 g, 15.4 mmol) was
added; the reaction mixture was refluxed until the evo-
lution of hydrogen sulfide ceased. After cooling, water
(20 mL) was added and the mixture was acidified with
hydrochloric acid. The thick solid mass which separated
out was collected by filtration, washed with water, dried
and recrystallized from ethanol to give 0.62g (32%) of
9k as a white solid: mp 190 ꢃC; IR (KBr) 3107, 1620,
1565, 1511, 1473, 1317, 1233, 1031, 951, 837, 729
(cmꢀ1); 1H NMR (DMSO-d6) d 8.15–8.11 (m, 2H),
7.87–7.71 (m, 4H), 7.55–7.37 (m, 3H), 5.8431 (br s, 2H).
In conclusion, a new series of 4-amino-3-[3-[4-(2-meth-
oxy or nitro phenyl)-1-piperazinyl]propyl]thio]-5-(sub-
stitutedphenyl)[1,2,4]triazoles 11a–t was synthesized and
tested in radioligand binding assays to evaluate their
affinity and selectivity for the 5-HT1A receptor with
respect to the a1-adrenergic receptor. Generally, these
compounds showed Ki values in the nanomolar range
and selectivity for the 5-HT1A receptor. 4-Amino-3-[3-
[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-
propyloxyphenyl)[1,2,4]triazole (11o) showed good
selectivity for the 5-HT1A receptor over both the a1-
adrenoceptor (ratio of 55) and the D2 receptor (ratio of
48). Synthetic and pharmacological work is in progress
to further evaluate the structure-affinity relationships in
this class of 5-HT1A receptor ligands.
Compounds 9d, 9h, 9i and 9j were prepared as 9k start-
ing from the suitable benzoic acid hydrazide.
4-Amino-5-(3-methoxyphenyl)-2,4-dihydro-3H[1,2,4]tria-
zole-3-thione (9d). Recrystallization from ethanol gave
0.97 g (57%) of 9d as a white solid: mp 199 ꢃC; IR (KBr)
3298, 3121,1623, 1579, 1529, 1477, 1316, 1212, 1177,
Experimental
Chemistry
1
954, 754 (cmꢀ1); H NMR (DMSO-d6) d 13.9531 (br s,
1H), 7.68–7.35 (m, 3H), 7.21–7.00 (m, 1H), 5.8031 (s,
2H), 3.80 (s, 3H).
Melting points were determined in a Gallemkamp
apparatus with a digital thermometer MFB-595 in glass
capillary tubes and are uncorrected. Infrared spectra
were recorded on a Perkin-Elmer FTIR 1600 spectro-
meter in KBr disks. Elemental analyses for C, H, N and
S were withinꢂ0.4% of theoretical values and were
performed on a Carlo Erba Elemental Analyzer Mod.
1108 apparatus. 1H NMR spectra were recorded at
200 MHz on a Varian Inova Unity 200 spectrometer in
DMSO-d6 solution. Chemical shifts are given in d values
(ppm), using tetramethylsilane as the internal standard;
coupling constants (J) are given in Hz. Signal multi-
plicities are characterized as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad signal).
4-Amino-5-(4-propyloxyphenyl)-2,4-dihydro-3H[1,2,4]tri-
azole-3-thione (9h). Recrystallization from ethanol gave
1.04 g (54%) of 9h as a white solid: mp 200 ꢃC; IR (KBr)
3294, 3115, 3017, 2939, 1611, 1512, 1177, 973, 840, 579
(cmꢀ1); 1H NMR (DMSO-d6) d 13.8131 (br s, 1H), 8.04–
7.90 (m, 2H), 7.14–6.99 (m, 2H), 5.7631 (br s, 2H), 4.00
(t, J=6.6, 2H), 1.89–1.64 (m, 2H), 0.99 (t, J=7.2, 3H).
4-Amino-5-(4-phenylsulphonylphenyl)-2,4-dihydro-3H-
[1,2,4]triazole-3-thione (9i). Recrystallization from etha-
nol gave 1.02g (40%) of 9i as a white solid: mp 190 ꢃC;
IR (KBr) 3305, 3200, 3101, 1623, 1465, 1308, 1156,
1
1106, 1031, 752(cm ꢀ1); H NMR (DMSO-d6) d 13.7831
(br s, 1H), 8.34–8.23 (m, 2H), 8.17–8.07 (m, 2H), 8.05–
7.95 (m, 2H), 7.76–7.58 (m, 3H), 5.8031 (s, 2H).
4-Amino-5-phenyl-2,4-dihydro-3H[1,2,4]triazole-3-thione
(9a), 4-amino-5-(2-chlorophenyl)-2,4-dihydro-3H[1,2,4]-
triazole-3-thione (9b), 4-amino-5-(4-methoxyphenyl)-
2,4-dihydro-3H[1,2,4]triazole-3-thione (9c), 4-amino-5
-(4-methylphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thione
(9e), 4-amino-5-(4-chlorophenyl)-2,4-dihydro-3H[1,2,4]-
triazole-3-thione (9f), 4-amino-5-(4-bromophenyl)-2,4-
dihydro-3H[1,2,4]triazole-3-thione (9g), 1-(3-chloropro-
pyl)-4-(2-methoxyphenyl)piperazine (10a), 1-(3-chlor-
opropyl) - 4 - (2- nitrophenyl)piperazine ( 10b), 1 - (2-
chloroethyl) - 4- (2- methoxyphenyl)piperazine ( 10c), 5 -
phenyl-2,4-dihydro-3H[1,2,4]triazole-3-thione (13a) and
5-(4-methoxyphenyl-2,4-dihydro-3H[1,2,4]triazole-3-
4-Amino-5-(4-phenoxymethylphenyl)-2,4-dihydro-3H-
[1,2,4]triazole-3-thione (9j). Recrystallization from etha-
nol gave 0.80 g (35%) of 9j as a white solid: mp 220 ꢃC;
IR (KBr) 3456, 3140, 2361, 1683, 1599, 1500, 1309,
1
1241, 1042, 753 (cmꢀ1); H NMR (DMSO-d6) d 13.7731
(br s, 1H), 8.11–7.96 (m, 2H), 7.65–7.50 (m, 2H), 7.40–
7.25 (m, 2H), 7.14–6.95 (m, 3H), 5.7331 (br s, 2H).
General procedure for the synthesis of [1,2,4]triazole de-
rivatives (11a–u) and 2,4-dihydro-3H[1,2,4]triazole-3-
thione derivatives (12a–s). To a solution of the appro-
priate 4-amino-5-substituted-2,4-dihydro-3H[1,2,4]tria-
zole-3-thione (9a–k) (2.0 mmol) in hot absolute ethanol
(10 mL), sodium hydroxide (0.08 g, 2.0 mmol) and
potassium iodide (0.01 g) were added. A solution of 1-
(3-chloropropyl)-4-(2-methoxyphenyl)piperazine (10a),
1-(3-chloropropyl)-4-(2-nitrophenyl)piperazine (10b) or
1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (10c)
(2.0 mmol) in absolute ethanol (5 mL) was added drop-
wise during 15 min. Then, the reaction mixture was
refluxed for 12h. After cooling, it was diluted with
thione
(13b)
were
prepared
as
previously
described.18,20ꢀ22,26ꢀ29
4-Amino-5-(1,10-biphenyl-4-yl)-2,4-dihydro-3H[1,2,4]tria-
zole-3-thione (9k). A solution of 1,10-biphenyl-4-carbo-
hydrazide (1.652g, 7.7 mmol) in absolute ethanol (50 mL)
was slowly added dropwise to a suspension of potassium
hydroxide (0.690 g, 10.5 mmol) in ethanol (30 mL).30
After stirring at room temperature for 1 h, carbon dis-
ulfide (0.799 g, 10.5 mmol) was added dropwise and the

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
319
water (30 mL), extracted with ether (4ꢄ20 mL). The
combined ethereal phases were washed with brine, dried
and removed in vacuo. The oily residue, which con-
tained both S- and N-substituted isomers, was purified
by flash-chromatography. Elution with pure ethyl ace-
tate yielded compounds 12a–s. Subsequent elution with
ethyl acetate containing 10% (v/v) methanol yielded
compounds 11a–u.
NMR (DMSO-d6) d 8.01–7.88 (m, 2H), 7.85–7.76 (m,
1H), 7.64–7.50 (m, 1H), 7.35–7.24 (m, 1H), 7.17–6.98
(m, 3H), 6.0631 (br s, 2H), 3.82 (s, 3H), 3.18 (t, J=7.4,
2H), 3.08–2.90 (m, 4H), 2.64–2.38 (m, 6H), 2.02–1.80
(m, 2H).
4-Amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
thio]-5-(3-methoxyphenyl)[1,2,4]triazole (11g). Flash
chromatography purification gave 0.34 g (37%) of 11g
as a white solid: mp 132 ꢃC; IR (KBr) 3450, 3067, 2934,
2822, 1589, 1497, 1460, 1239, 1025, 745 (cmꢀ1); 1H
NMR (DMSO-d6) d 7.62–7.50 (m, 2H), 7.48–7.38 (m,
4-Amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]prop-
yl]thio]-5-phenyl[1,2,4]triazole (11a). Flash chromato-
graphy purification gave 0.42g (50%) of 11a as a white
solid: mp 135 ꢃC; IR (KBr) 3331, 3213, 3061, 2941,
2821, 1590, 1498, 1461, 1240, 743 (cmꢀ1); 1H NMR
(DMSO-d6) d 7.98–7.90 (m, 2H), 7.52–7.40 (m, 3H),
6.95–6.76 (m, 4H), 6.0731 (br s, 2H), 3.72 (s, 3H), 3.16 (t,
J=7.4, 2H), 3.04–2.84 (m, 4H), 2.60–2.35 (m, 6H),
1.95–1.75 (m, 2H).
31
1H), 7.13–7.02(m, 1H), 6.99–6.79 (m, 4H), 6.12 (br s,
2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.20 (t, J=7.2, 2H),
3.08–2.85 (m, 4H), 2.67–2.37 (m, 6H), 2.02–1.81 (m,
2H).
4-Amino-5-(3-methoxyphenyl)-3-[3-[4-(2-nitrophenyl)-1-
piperazinyl]propyl]thio][1,2,4]triazole (11h). Flash chro-
matography purification gave 0.28 g (30%) of 11h as a
yellowish solid: mp 120 ꢃC; IR (KBr) 3334, 3209, 3059,
2943, 2812, 1600, 1524, 1478, 1368, 1231, 737 (cmꢀ1);
1H NMR (DMSO-d6) d 7.82–7.72 (m, 1H), 7.63–7.48
(m, 3H), 7.45–7.23 (m, 2H), 7.18–7.00 (m, 2H), 6.1131
(br s, 2H), 3.80 (s, 3H), 3.19 (t, J=7.2, 2H), 3.08–2.90
(m, 4H), 2.60–2.37 (m, 6H), 2.01–1.80 (m, 2H).
4-Amino-3-[3-[4-(2-nitrophenyl)-1-piperazinyl]propyl]thio]-
5-phenyl[1,2,4]triazole (11b). Flash chromatography
purification gave 0.47 g (54%) of 11b as a yellow solid:
mp 147 ꢃC; IR (KBr) 3332, 3075, 2940, 2842, 1605,
1
1567, 1521, 1445, 1337, 700 (cmꢀ1); H NMR (DMSO-
d6) d 8.03–7.93 (m, 2H), 7.82–7.75 (m, 1H), 7.63–7.46
(m, 4H), 7.33–7.27 (m, 1H), 7.17–7.05 (m, 1H), 6.1231
(br s, 2H), 3.20 (t, J=7.4, 2H), 3.09–2.92 (m, 4H), 2.60–
2. 35 (m, 6H), 2.02–1.78 (m, 2H).
4-Amino-35-[3-[4-(2-methoxyphenyl)-1-piperazinyl]pro-
pyl]thio]-5-(4-methylphenyl)[1,2,4]triazole (11i). Flash
chromatography purification gave 0.45 g (51%) of 11i as
a white solid: mp 170 ꢃC; IR (KBr) 3324, 3130, 2936,
2830, 1592, 1498, 1444, 1237, 1117, 741 (cmꢀ1); 1H
NMR (DMSO-d6) d 7.95–7.83 (m, 2H), 7.39–7.28 (m,
2H), 7.01–6.80 (m, 4H), 6.0831 (br s, 2H), 3.77 (s, 3H),
3.20 (t, J=7.4, 2H), 3.07–2.88 (m, 4H), 2.63–2.40 (m,
6H), 2.37 (s, 3H), 2.01–1.80 (m, 2H).
4-Amino-5-(2-chlorophenyl)-3-[3-[4-(2-methoxyphenyl)-1-
piperazinyl]propyl]thio][1,2,4]triazole (11c). Flash chro-
matography purification gave 0.38 g (42%) of 11c as a
white solid: mp 137 ꢃC; IR (KBr) 3242, 3064, 2935,
2816, 1591, 1497, 1451, 1239, 744 (cmꢀ1); 1H NMR
(DMSO-d6) d 7.63–7.38 (m, 4H), 6.96–6.74 (m, 4H),
5.8031 (br s, 2H), 3.72 (s, 3H), 3.18 (t, J=7.4, 2H), 3.05–
2.75 (m, 4H), 2.65–2.28 (m, 6H), 2.00–1.78 (m, 2H).
4-Amino-5-(4-methylphenyl)-3-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]thio][1,2,4]triazole (11j). Flash chroma-
tography purification gave 0.50 g (55%) of 11j as a
yellow solid: mp 172 ꢃC; IR (KBr) 3324, 3134, 2945,
2829, 1604, 1524, 1445, 1359, 1234, 1120, 744 (cmꢀ1);
1H NMR (DMSO-d6) d 7.94–7.83 (m, 2H), 7.82–7.72
(m, 1H), 7.62–7.48 (m, 1H), 7.37–7.23 (m, 3H), 7.18–
7.04 (m, 1H), 6.0731 (br s, 2H), 3.18 (t, J=7.2, 2H),
2.89–3.04 (m, 4H), 2.58–2.40 (m, 6H), 2.36 (s, 3H),
2.01–1.80 (m, 2H).
4-Amino-5-(2-chlorophenyl)-3-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]thio][1,2,4]triazole (11d). Flash chroma-
tography purification gave 0.31 g (33%) of 11d as a
yellowish oil; IR (KBr) 3342, 3184, 2946, 2824, 1604,
1
1517, 1449, 1343, 767 (cmꢀ1); H NMR (DMSO-d6) d
7.81–7.70 (m, 1H), 7.68–7.38 (m, 5H), 7.35–7 21 (m,
1H), 7.16–7.00 (m, 1H), 5.7931 (br s, 2H), 3.17 (t, J=7.4,
2H), 3.08–2.85 (m, 4H), 2.63–2.30 (m, 6H), 1.98–1.79
(m, 2H).
4-Amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
thio]-5-(4-methoxyphenyl)[1,2,4]triazole (11e). Flash
chromatography purification gave 0.34 g (41%) of 11e
as a white solid: mp 138 ꢃC; IR (KBr) 3419, 2934, 2817,
1612, 1499, 1453,1242, 1024, 746 (cmꢀ1); 1H NMR
(DMSO-d6) d 8.02–7.88 (m, 2H), 7.15–7.01 (m, 2H),
6.99–6.77 (m, 4H), 6.0531 (br s, 2H), 3.82 (s, 3H), 3.77
(s, 3H), 3.18 (t, J=7.2, 2H), 3.04–2.80 (m, 4H), 2.65–
2.35 (m, 6H), 2.03–1.80 (m, 2H).
4-Amino-5-(4-chlorophenyl)-3-[3-[4-(2-methoxyphenyl)-1-
piperazinyl]propyl]thio][1,2,4]triazole (11k). Flash chro-
matography purification gave 0.22 g (24%) of 11k as a
white solid: mp 167 ꢃC; IR (KBr) 3321, 3125, 2934,
2832, 1592, 1499, 1439, 1238, 1117, 745 (cmꢀ1); 1H
NMR (DMSO-d6) d 8.09–7.96 (m, 2H), 7.65–7.54 (m,
2H), 7.01–6.79 (m, 4H), 6.1331 (br s, 2H), 3.77 (s, 3H),
3.21 (t, J=7.2, 2H), 3.04–2.79 (m, 4H), 2.63–2.36 (m,
6H), 2.03–1.80 (m, 2H).
4-Amino-5-(4-methoxyphenyl)-3-[3-[4-(2-nitrophenyl)-1-
piperazinyl]propyl]thio][1,2,4]triazole (11f). Flash chro-
matography purification gave 0.42g (45%) of 11f as a
yellow solid: mp 172 ꢃC; IR (KBr) 3455, 3322, 2938,
2837, 1605, 1527, 1437, 1382, 1258, 747 (cmꢀ1); 1H
4-Amino-5-(4-chlorophenyl)-3-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]thio][1,2,4]triazole (11l). Flash chroma-
tography purification gave 0.33 g (35%) of 11l as a
yellow solid: mp 146 ꢃC; IR (KBr) 3319, 3111, 2948,
2818, 1604, 1563, 1512, 1436, 1300, 1232, 1088, 830, 740

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
320
(cmꢀ1); 1H NMR (DMSO-d6) d 8.11–7.96 (m, 2H),
7.84–7.73 (m, 1H), 7.67–7.47 (m, 3H), 7.36–7.23 (m,
1H), 7.16–7.04 (m, 1H), 6.1431 (br s, 2H), 3.21 (t, J=7.4,
2H), 3.08–2.90 (m, 4H), 2.59–2.35 (m, 6H), 2.01–1.80
(m, 2H).
3327, 2938, 2817, 1602, 1528, 1446, 1314, 1154, 1115,
1
752(cm ꢀ1); H NMR (DMSO-d6) d 8.31–8.19 (m, 2H),
8.16–7.96 (m, 4H), 7.83–7.50 (m, 5H), 7.36–7.25 (m,
1H), 7.16–7.05 (m, 1H), 6.1731 (br s, 2H), 3.21 (t, J=7.2,
2H), 3.05–2.89 (m, 4H), 2.58–2.37 (m, 6H), 2.01–1.80
(m, 2H).
4-Amino-5-(4-bromophenyl)-3-[3-[4-(2-methoxyphenyl)-
1-piperazinyl]propyl]thio][1,2,4]triazole (11m). Flash
chromatography purification gave 0.34 g (34%) of 11m
as a white solid: mp 167 ꢃC; IR (KBr) 3320, 3120, 2933,
2831, 1590, 1499, 1437, 1237, 1116, 744 (cmꢀ1); 1H
NMR (DMSO-d6) d 8.06–7.90 (m, 2H), 7.78–7.67 (m,
2H), 7.02–6.78 (m, 4H), 6.1431 (br s, 2H), 3.77 (s, 3H),
3.21 (t, J=7.0, 2H), 3.08–2.77 (m, 4H), 2.64–2.35 (m,
6H), 2.02–1.80 (m, 2H).
4-Amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
thio]-5-(4-phenoxymethylphenyl)[1,2,4]triazole
(11s).
Flash chromatography purification gave 0.39 g (37%)
of 11s as a white solid: mp 151 ꢃC; IR (KBr) 3249, 3114,
2934, 2816, 1593, 1500, 1450, 1243, 1022, 752 (cmꢀ1);
1H NMR (DMSO-d6) d 8.03–7.99 (m, 2H), 7.60–7.56
(m, 2H), 7.34–7.26 (m, 2H), 7.05–6.86 (m, 7H), 6.1231
(br s, 2H), 5.18 (s, 2H), 3.76 (s, 3H), 3.20 (t, J=7.00,
2H), 2.95 (br s, 4H), 2.50–2.43 (m, 6H), 1.99–1.88 (m,
2H).
4-Amino-5-(4-bromophenyl)-3-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]thio][1,2,4]triazole (11n). Flash chro-
matography purification gave 0.30 g (29%) of 11n as a
yellow solid: mp 141 ꢃC; IR (KBr) 3321, 3109, 2946,
2829, 1601, 1522, 1438, 1363, 1231, 1118, 829, 742
(cmꢀ1); 1H NMR (DMSO-d6) d 8.04–7.92(m, 2H), 7.84–
7.66 (m, 3H), 7.64–7.50 (m, 1H), 7.37–7.25 (m, 1H), 7.17–
7.05 (m, 1H), 6.1431 (br s, 2H), 3.21 (t, J=7.4, 2H), 3.07–
2.90 (m, 4H), 2.65–2.35 (m, 6H), 2.02–1.80 (m, 2H).
4-Amino-5-(1,10 -biphenyl-4-yl)-3-[3-[4-(2-methoxyphe-
nyl)-1-piperazinyl]propyl]thio][1,2,4]triazole (11t). Flash
chromatography purification gave 0.32g (32%) of 11t
as a white solid: mp 145–147 ꢃC; H NMR (DMSO-d6)
1
d 8.20–8.03 (m, 2H), 7.91–7.63 (m, 4H), 7.88–7.60 (m,
3H), 7.01–6.78 (m, 4H), 6.1831 (br s, 2H), 3.77 (s, 3H),
3.22 (t, J=7.2, 2H), 3.08–2.77 (m, 4H), 2.69–2.32 (m,
6H), 2.03–1.81 (m, 2H).
4-Amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
thio]-5-(4-propyloxyphenyl)[1,2,4]triazole (11o). Flash
chromatography purification gave 0.34 g (35%) of 11o
as a white solid: mp 141 ꢃC; IR (KBr) 3330, 3058, 2936,
2824, 1610, 1499, 1447, 1243, 1119, 747 (cmꢀ1); 1H
NMR (DMSO-d6) d 7.98–7.86 (m, 2H), 7.13–7.01 (m,
2H), 6.98–6.80 (m, 4H), 6.0631 (br s, 2H), 3.99 (t, J=6.4,
2H), 3.76 (s, 3H), 3.18 (t, J=7.4, 2H), 3.04–2.89 (m,
4H), 2.63–2.39 (m, 6H), 2.01–1.82 (m, 2H), 1.80–1.65
(m, 2H), 0.99 (t, J=7.4, 3H).
4-Amino-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
thio]-5-(4-propyloxyphenyl)[1,2,4]triazole (11u). Flash
chromatography purification gave 0.54 g (58%) of 11u
as a white solid: mp 151 ꢃC; IR (KBr) 3241, 3114, 2957,
2818, 1611, 1503, 1452, 1242, 1024, 747 (cmꢀ1); 1H
NMR (DMSO-d6) d 7.97–7.92(m, 2H), 7.10–7.02(m,
2H), 6.94–6.79 (m, 4H), 6.0931 (br s, 2H), 3.99 (t, J=6.6,
2H), 3.75 (s, 3H), 3.30 (t, J=6.6, 2H), 2.99–2.83 (m,
4H), 2.70 (t, J=6.6, 2H) 2.61–2.45 (m, 4H), 1.85–1.66
(m, 2H), 0.99 (t, J=7.2, 3H).
4-Amino-3-[3-[4-(2-nitrophenyl)-1-piperazinyl]propyl]thio]-
5-(4-propyloxyphenyl)[1,2,4]triazole (11p). Flash chro-
matography purification gave 0.43 g (43%) of 11p as a
yellow solid: mp 149 ꢃC; IR (KBr) 3329, 2949, 2839,
4-Amino-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
5-phenyl-2,4-dihydro-3H[1,2,4]triazole-3-thione
(12a).
Flash chromatography purification gave 0.13 g (15%)
of 12a as a white solid: mp 112–114 ꢃC; IR (KBr) 3238,
3126, 2938, 2817, 1635, 1586, 1497, 1451, 1245, 1027,
1
1606, 1520, 1422, 1348, 1240, 1121, 841, 742 (cmꢀ1); H
NMR (DMSO-d6) d 7.98–7.87 (m, 2H), 7.84–7.73 (m,
1H), 7.63–7.50 (m, 1H), 7.36–7.23 (m, 1H), 7.17–6.98
(m, 3H), 6.0631 (br s, 2H), 3.99 (t, J=6.2, 2H), 3.18 (t,
J=7.4, 2H), 3.08–2.83 (m, 4H), 2.60–2.37 (m, 6H), 2.02–
1.82 (m, 2H), 1.80–1.63 (m, 2H), 0.99 (t, J=7.2, 3H).
1
744 (cmꢀ1); H NMR (DMSO-d6) d 8.10–7.95 (m, 2H),
7.63–7.43 (m, 3H), 6.98–6.75 (m, 4H), 5.8531 (br s, 2H),
4.21 (t, J=7.0, 2H), 3.72 (s, 3H), 3.03–2.70 (m, 4H),
2.60–2.25 (m, 6H), 2.05–1.80 (m, 2H).
4-Amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
thio]-5-(4-phenylsulphonylphenyl)[1,2,4]triazole
4-Amino-2-[3-[4-(2-nitrophenyl)-1-piperazinyl]propyl]-5-
phenyl-2,4-dihydro-3H[1,2,4]triazole-3-thione
(11q).
(12b).
Flash chromatography purification gave 0.28 g (25%)
of 11q as a white solid: mp 199 ꢃC; IR (KBr) 3453, 3330,
2933, 2814, 1596, 1497, 1445, 1237, 1152, 1116, 750
(cmꢀ1); 1H NMR (DMSO-d6) d 8.33–8.20 (m, 2H),
8.18–7.94 (m, 4H), 7.77–7.58 (m, 3H), 7.00–6.78 (m,
4H), 6.2031 (br s, 2H), 3.76 (s, 3H), 3.22 (t, J=7.0, 2H),
3.07–2.85 (m, 4H), 2.63–2.37 (m, 6H), 2.01–1.80 (m,
2H).
Flash chromatography purification gave 0.18 g (20%)
of 12b as a yellow solid: mp 95–98 ꢃC; IR (KBr) 3281,
3060, 2930, 2819, 1646, 1604, 1519, 1456, 1332, 1228,
1
694 (cmꢀ1); H NMR (DMSO-d6) d 8.10–7.91 (m, 2H),
7.85–7.70 (m, 1H), 7.69–7.42(m, 3H), 7.35–7.02 (m,
1H), 7.17–7.00 (m, 1H), 5.8531 (br s, 2H), 4.21 (t, J=7.0,
2H), 3.07–2.70 (m, 4H), 2.65–2.25 (m, 6H), 2.06–1.80
(m, 2H).
4-Amino-3-[3-[4-(2-nitrophenyl)-1-piperazinyl]propyl]-
thio]-5-(4-phenylsulphonylphenyl)[1,2,4]triazole (11r).
Flash chromatography purification gave 0.30 g (26%)
of 11r as a yellow solid: mp 178 ꢃC; IR (KBr) 3450,
4-Amino-5-(2-chlorophenyl)-2-[3-[4-(2-methoxyphenyl)-1-pi-
perazinyl]propyl] - 2,4- dihydro - 3H[1,2,4]triazole- 3 - thione
(12c). Flash chromatography purification gave 0.11 g
(12%) of 12c as a yellow solid: mp 178 ꢃC; IR (KBr)

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
321
3277, 3059, 2930, 2816, 1635, 1500, 1450, 1238, 1026,
1
3299, 3164, 2931, 2817, 1611, 1497, 1444, 1335, 1238,
1028, 750 (cmꢀ1); 1H NMR (DMSO-d6) d 7.98–7.85 (m,
2H), 7.42–7.30 (m, 2H), 7.00–6.78 (m, 4H), 5.8531 (br s,
2H), 4.23 (t, J=6.8, 2H), 3.76 (s, 3H), 3.08–2.78 (m,
4H), 2.68–2.24 (m+s, 6H+3H), 2.10–1.85 (m, 2H).
744 (cmꢀ1); H NMR (DMSO-d6) d 7.72–7.45 (m, 4H),
7.00–6.78 (m, 4H), 5.6431 (br s, 2H), 4.24 (t, J=7.0, 2H),
3.76 (s, 3H), 3.10–2.85 (m, 4H), 2.65–2.35 (m, 6H),
2.10–1.87 (m, 2H).
4-Amino-5-(2-chlorophenyl)-2-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]-2,4-dihydro-3H[1,2,4]triazole-3-thione
(12d). Flash chromatography purification gave 0.16 g
(17%) of 12d as a yellow solid: mp 126 ꢃC; IR (KBr)
3263, 3069, 2930, 2819, 1641, 1601, 1519, 1448, 1336,
4-Amino-5-(4-methylphenyl)-2-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]-2,4-dihydro-3H[1,2,4]triazole-3-thione
(12j). Flash chromatography purification gave 0.17 g
(19%) of 12j as a yellow solid: mp 128 ꢃC; IR (KBr)
3294, 3070, 2928, 2827, 1604, 1513, 1457, 1341, 1231,
1125, 746 (cmꢀ1); 1H NMR (DMSO-d6) d 8.06–7.90 (m,
2H), 7.86–7.70 (m, 1H), 7.64–7.46 (m, 1H), 7.43–7.22
(m, 3H), 7.18–7.03 (m, 1H), 5.8631 (br s, 2H), 4.23 (t,
J=6.8, 2H), 3.10–2.85 (m, 4H), 2.65–2.30 (m+s,
6H+3H), 2.10–1.85 (m, 2H).
1
1220, 1034, 769 (cmꢀ1); H NMR (DMSO-d6) d 7.88–
7.78 (m, 1H), 7.75–7.45 (m, 5H), 7.42–7.25 (m, 1H) 7.20–
7.03 (m, 1H), 5.6531 (br s, 2H), 4.24 (t, J=6.8, 2H), 2.79–
3.18 (m, 4H), 2.70–2.30 (m, 6H), 2.18–1.87 (m, 2H).
4-Amino-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
5-(4-methoxyphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-
thione (12e). Flash chromatography purification gave
0.11 g (12%) of 12e as a white solid: mp 98 ꢃC; IR (KBr)
3280, 2933, 2815, 1611, 1499, 1453, 1243, 1022, 833, 744
(cmꢀ1); 1H NMR (DMSO-d6) d 8.10–7.95 (m, 2H),
7.18–7.03 (m, 2H), 7.01–6.78 (m, 4H), 5.8531 (br s, 2H),
4.22 (t, J=7.0, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 3.08–2.75
(m, 4H), 2.72–2.32 (m, 6H), 2.10–1.85 (m, 2H).
4-Amino-5-(4-chlorophenyl)-2-[3-[4-(2-methoxyphenyl)-1-pi-
perazinyl]propyl] - 2,4- dihydro - 3H[1,2,4]triazole- 3 - thione
(12k). Flash chromatography purification gave 0.15 g
(16%) of 12k as a white solid: mp 106 ꢃC; IR (KBr):
3244, 3132, 2943, 2818, 1592, 1494, 1448, 1242, 1093,
1030, 746 (cmꢀ1); 1H NMR (DMSO-d6) d 8.16–8.00 (m,
2H), 7.70–7.56 (m, 2H), 7.00–6.78 (m, 4H), 5.8931 (br s,
2H), 4.24 (t, J=7.0, 2H), 3.76 (s, 3H), 3.05–2.80 (m,
4H), 2.65–2.30 (m, 6H), 2.10–1.87 (m, 2H).
4-Amino-5-(4-methoxyphenyl)-2-[3-[4-(2-nitrophenyl)-1-
piperazinyl]propyl]-2,4-dihydro-3H[1,2,4]triazole-3-thione
(12f). Flash chromatography purification gave 0.17 g
(18%) of 12f as a yellow solid: mp 112 ꢃC; IR (KBr):
3277, 2934, 2826, 1583, 1498, 1458, 1231, 1025, 751
(cmꢀ1); 1H NMR (DMSO-d6) d 8.07–7.90 (m, 2H),
7.85–7.73 (m, 1H), 7.64–7.48 (m, 1H), 7.36–7.22 (m,
1H), 7.18–6.98 (m, 3H), 5.8631 (br s, 2H), 4.22 (t, J=6.8,
2H), 3.83 (s, 3H), 3.76 (s, 3H), 3.12–2.89 (m, 4H), 2.65–
2.30 (m, 6H), 2.10–1.85 (m, 2H).
4-Amino-5-(4-chlorophenyl)-2-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]-2,4-dihyro-3H[1,2,4]triazole-3-thione
(12l). Flash chromatography purification gave 0.16 g
(17%) of 12l as a yellow solid: mp 112–114 ꢃC; IR (KBr)
3310, 2945, 2824, 1604, 1516, 1454, 1347, 1233, 1092,
1
838, 748 (cmꢀ1); H NMR (DMSO-d6) d 8.24–7.95 (m,
2H), 7.88–7.75 (m, 1H), 7.72–7.45 (m, 3H), 7.38–7.22
(m, 1H), 7.20–7.03 (m, 1H), 5.9031 (br s, 2H), 4.25 (t,
J=6.8, 2H), 3.15–2.78 (m, 4H), 2.67–2.28 (m, 6H),
2.13–1.83 (m, 2H).
4-Amino-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
5-(3-methoxyphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-
thione (12g). Flash chromatography purification gave
0.16 g (18%) of 12g as a white solid: mp 145 ꢃC; IR
(KBr): 3265, 3118, 2989, 2935, 2826, 1583, 1497, 1458,
4-Amino-5-(4-bromophenyl)-2-[3-[4-(2-methoxyphenyl)-1
- piperazinyl]propyl] - 2,4 - dihydro - 3H[1,2,4]triazole - 3 -
thione (12m). Flash chromatography purification gave
0.20 g (20%) of 12m as a colourless oil; IR (KBr) 3273,
2930, 2814, 1593, 1497, 1451, 1238, 1010, 746 (cmꢀ1);
1H NMR (DMSO-d6) d 8.06–7.90 (m, 2H), 7.85–7.70
(m, 2H), 7.01–6.77 (m, 4H), 5.8931 (br s, 2H), 4.24 (t,
J=6.8 Hz, 2H), 3.76 (s, 3H), 3.10–2.75 (m, 4H), 2.65–
2.32 (m, 6H), 2.13–1.85 (m, 2H).
1
1231, 1026, 751 (cmꢀ1); H NMR (DMSO-d6) d 7.65–
7.55 (m, 2H), 7.52–7.38 (m, 1H), 7.18–7.07 (m, 1H),
7.00–6.78 (m, 4H), 5.8931 (br s, 2H), 4.24 (t, J=7.0, 2H),
3.80 (s, 3H), 3.75 (s, 3H), 3.10–2.73 (m, 4H), 2.65–2.28
(m, 6H), 2.10–1.85 (m, 2H).
4-Amino-5-(3-methoxyphenyl)-2-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl] - 2,4 - dihydro - 3H[1,2,4]triazole - 3 - thione
(12h). Flash chromatography purification gave 0.19 g
(20%) of 12h as a yellow solid: mp 145–147 ꢃC; IR
(KBr) 3318, 2934, 2825, 1609, 1522, 1456, 1339, 1229,
1040, 747 (cmꢀ1); 1H NMR (DMSO-d6) d 7.79–7.68 (m,
1H), 7.62–7.35 (m, 4H), 7.33–7.20 (m, 1H), 7.15–7.00
(m, 2H), 5.8531 (br s, 2H), 4.20 (t, J=7.0, 2H), 3.77 (s,
3H), 3.08–2.85 (m, 4H), 2.65–2.30 (m, 6H), 2.06–1.84
(m, 2H).
4-Amino-5-(4-bromophenyl)-2-[3-[4-(2-nitrophenyl)-1-pi-
perazinyl]propyl]-2,4-dihydro-3H[1,2,4]triazole-5-thione
(12n). Flash chromatography purification gave 0.21 g
(20%) of 12n as a yellow solid: mp 146 ꢃC; IR (KBr)
3268, 3170, 2954, 2823, 1604, 1514, 1443, 1343, 1233,
1
1012, 831, 746 (cmꢀ1); H NMR (DMSO-d6) d 7.90–
8.01 (m, 2H), 7.65–7.79 (m, 3H), 7.45–7.58 (m, 1H),
7.20–7.32 (m, 1H), 7.01–7.16 (m, 1H), 5.8531 (br s, 2H),
4.20 (t, J=7.0, 2H), 2.85–3.06 (m, 4H), 2.30–2.63 (m,
6H), 1.85–2.08 (m, 2H).
4-Amino-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-
5-(4-methylphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thione
(12i). Flash chromatography purification gave 0.15 g
(17%) of 12i as a white solid: mp 114 ꢃC; IR (KBr)
4-Amino-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]
-5-(4-propyloxyphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-
thione (12o). Flash chromatography purification gave
0.11 g (12%) of 12o as a white solid: mp 94 ꢃC; IR (KBr)

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
322
3281, 3130, 2933, 2823, 1646, 1612, 1499, 1458, 1245,
1026, 746 (cmꢀ1); 1H NMR (DMSO-d6) d 8.04–7.90 (m,
2H), 7.16–7.03 (m, 2H), 7.00–6.78 (m, 4H), 5.8531 (br s,
2H), 4.22 (t, J=7.0, 2H), 4.00 (t, J=6.6, 2H), 3.75 (s,
3H), 3.03–2.82 (m, 4H), 2.63–2.33 (m, 6H), 2.09–1.85
(m, 2H), 1.84–1.65 (m, 2H), 0.99 (t, J=7.6, 3H).
and water (50 mL) was added. The mixture was then
extracted with ethyl acetate (4ꢄ50 mL) and the com-
bined organic phases were washed with brine and dried
over anhydrous sodium sulphate. Distillation of the
solvent under vacuum gave an oily residue which was
flash-chromatographed on silica gel 60 (Merck, Darm-
stadt, Germany) using ethyl acetate as eluent. Fractions
which were homogeneous on TLC were combined and
dried over anhydrous sodium sulphate. Distillation of
the solvent under vacuum gave 0.60 g (52%) of an oily
residue of pure 6a which slowly crystallized in a white
solid: mp 100 ꢃC; IR (KBr) 3447, 3062, 2937, 2815,
4-Amino-2-[3-[4-(2-nitrophenyl)-1-piperazinyl]propyl]-5-
(4 - propyloxyphenyl) - 2,4 - dihydro - 3H[1,2,4]triazole - 3 -
thione (12p). Flash chromatography purification gave
0.15 g (15%) of 12p as a yellowish oil; IR (KBr) 3282,
2933, 2816, 1607, 1498, 1450, 1250, 968, 835, 745
(cmꢀ1); 1H NMR (DMSO-d6) d 8.14–7.90 (m, 2H),
7.86–7.73 (m, 1H), 7.64–7.50 (m, 1H), 7.38–7.22 (m,
1H), 7.20–7.01 (m, 3H), 5.8531 (br s, 2H), 4.22 (t, J=7.0,
2H), 4.00 (t, J=6.6, 2H), 3.08–2.84 (m, 4H), 2.64–2.33
(m, 6H), 2.08–1.85 (m, 2H), 1.82–1.60 (m, 2H), 0.99 (t,
J=7.4, 3H).
1
1589, 1499, 1458, 1241, 1125, 1021, 749, 728 (cmꢀ1); H
NMR (DMSO-d6) d 8.03–7.90 (m, 2H), 7.57–7.42 (m,
3H), 7.00–6.79 (m, 4H), 3.76 (s, 3H), 3.19 (t, J=7.2,
2H), 3.04–2.87 (m, 4H), 2.63–2.36 (m, 6H), 2.01–1.79
(m, 2H).
3-[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl]thio]-5-
(4-methoxyphenyl)[1,2,4] triazole (14b). The synthesis of
this compound was accomplished following the method
used for 14a, starting from 5-(4-methoxyphenyl)-2,4-
dihydro-3H[1,2,4]triazole-3-thione (13b). Flash chroma-
tography purification on silica gel 60 using ethyl acetate
as eluent afforded 0.82g (66%) of 14b as a white solid:
mp 83 ꢃC; IR (KBr) 3100, 2938, 2816, 1614, 1502, 1453,
4-Amino-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]
-5-(4-phenylsulphonylphenyl)-2,4-dihydro-3H[1,2,4]tria-
zole-3-thione (12q). Flash chromatography purification
gave 0.11 g (10%) of 12q as a colourless oil; IR (KBr)
3290, 2929, 1669, 1499, 1454, 1284, 1154, 745 (cmꢀ1);
1H NMR (DMSO-d6) d 8.36–8.22 (m, 2H), 8.20–8.07
(m, 2H), 8.06–7.92 (m, 2H), 7.80–7.58 (m, 3H), 7.00–
6.78 (m, 4H), 5.8931 (br s, 2H), 4.25 (t, J=7.0, 2H), 3.75
(s, 3H), 3.05–2.72 (m, 4H), 2.65–2.30 (m, 6H), 2.10–1.85
(m, 2H).
1
1245, 1179, 1027, 751 (cmꢀ1). H NMR (DMSO-d6) d
7.97–7.83 (m, 2H), 7.15–7.02 (m, 2H), 7.00–6.77 (m,
4H), 3.81 (s, 3H), 3.76 (s, 3H), 3.17 (t, J=7.4, 2H),
3.04–2.75 (m, 4H), 2.65–2.34 (m, 6H), 2.00–1.77 (m,
2H).
4-Amino-2-[3-[4-(2-nitrophenyl)-1-piperazinyl]propyl]-5-
(4-phenylsulphonylphenyl)-2,4-dihydro-3H[1,2,4]triazole-
3-thione (12r). Flash chromatography purification gave
0.15 g (13%) of 12r as a yellow solid: mp 184 ꢃC; IR
(KBr) 3285, 2920, 2817, 1602, 1516, 1448, 1286, 1154,
Pharmacology
Binding experiments. Binding assays were performed on
male CRL:CD(SD)BR-COBS rats weighing about
150 g. The animals were killed by decapitation, and their
brains were rapidly dissected (hippocampus for 5-
HT1AR; cortex for a1AR; striatum for D2), frozen and
stored at ꢀ80 ꢃC until the day of the assay.
1
841, 743 (cmꢀ1); H NMR (DMSO-d6) d 8.36–8.22 (m,
2H), 8.20–8.07 (m, 2H), 8.06–7.92 (m, 2H), 7.84–7.45
(m, 5H), 7.35–7.21 (m, 1H), 7.17–7.03 (m, 1H), 5.9031
(br s, 2H), 4.24 (t, J=7.0, 2H), 3.06–2.85 (m, 4H), 2.63–
2.30 (m, 6H), 2.07–1.84 (m, 2H).
4-Amino-2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5
-(4-propyloxyphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-
thione (12s). Flash chromatography purification gave
0.26 g (28%) of 12s as a white solid: mp 122 ꢃC; IR
(KBr) 3268, 3155, 2938, 2876, 2815, 1613, 1501, 1452,
Tissue were homogenized in about 50 volumes of ice-
cold 50 mM Tris–HCl buffer (pH 7.4) using an Ultra
Turrax TP-1810 (2ꢄ20 s) and centrifuged at 50,000g for
10 min (Beckman model J-21B refrigerated centrifuge).
The pellet was resuspended in the same volume of fresh
buffer, incubated at 37 ꢃC for 10 min and centrifuged
again at 50,000g for 10 min. The pellet was then washed
once by resuspension in fresh buffer and centrifuged as
before. The pellet was then resuspended in the appro-
priate incubation buffer [50 mM Tris–HCl (pH 7.7)
containing 10 mM pargyline and, for the 5-HT1A recep-
tor, 4 mM CaCl2 or, for the a1-adrenoceptor, 0.1%
ascorbic acid; 50 mM Tris–HCl (pH 7.1) containing
10 mM pargyline, 120 mM NaCl, 5 mM KCl, 2 mM
CaCl2, 1 mM MgCl2 and 0.1% ascorbic acid for D2
receptor] just before the binding assay.
1
1258, 1240, 1177, 976, 745 (cmꢀ1); H NMR (DMSO-
d6) d 8.00–7.96 (m, 2H), 7.10–7.03 (m, 2H), 6.92–6.85
(m, 4H), 5.8731 (br s, 2H), 4.32 (t, J=6.8, 2H), 4.00 (t,
J=6.6, 2H), 3.76 (s, 3H), 3.10–2.87 (m, 4H), 2.80 (t,
J=6.8, 2H), 2.67–2.55 (m, 4H), 1.84–1.66 (m, 2H), 0.98
(t, J=7.4, 3H).
3-[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl]thio]-5-
phenyl[1,2,4]triazole (14a). To a solution of 5-phenyl-
2,4-dihydro-3H[1,2,4]triazole-3-thione (13a) (0.50 g,
2.82 mmol) in hot absolute ethanol (20 mL), potassium
hydroxide (0.16 g, 2.82 mmol) and potassium iodide
(0.01 g) were added. A solution of 1-(3-chloropropyl)-4-
(2-methoxyphenyl)piperazine (10a) (0.76 g, 2.82 mmol)
in absolute ethanol (8 mL) was added dropwise during
45 min. Then, the reaction mixture was refluxed for 6 h.
After cooling, the solvent was removed under vacuum
Binding assays were performed as previously descri-
bed.32 Briefly, the following incubation conditions were
used: 5-HT1A receptor: [3H]-8-OH-DPAT (specific
activity 157 Ci/mmol, NEN) final concentration 1 nM,
30 min at 25 ꢃC (non-specific binding: 5-HT 10 mM); a1-

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M. C. Sarva et al. / Bioorg. Med. Chem. 10 (2002) 313–323
323
adrenoceptor: [3H]prazosin (specific activity 71.8 Ci/
mmol, NEN) final concentration 0.2nM, 30 min at
25 ꢃC (non-specific binding: prazosin 1 mM); D2 recep-
tor: [3H]spiperone (specific activity 19.0 Ci/mmol, NEN)
final concentration 0.2nM, 15 min at 37 C (non-specific
binding: (ꢀ)-sulpiride 100 mM).
8. Nelson, D. L. Pharmacol. Biochem. Behav. 1991, 40, 1041.
9. Glennon, R. A. Drug. Dev. Res. 1992, 26, 251.
10. Trumpp-Kallmayer, S.; Hoflack, J.; Bruinvels, A.; Hibert,
M. J. Med. Chem. 1992, 35, 3448.
11. Raghupathi, R. K.; Rydelek-Fitzgerald, L.; Teitler, M.;
Glennon, R. A. J. Med. Chem. 1991, 34, 2633.
12. Stanisic, D.; Hanconk, A. A.; Meyer, M.; De Bernardis,
J. F. FASEB J. 1988, 2, A.
ꢃ
Incubation was stopped by rapid filtration under
vacuum through GF/B filters which were then washed
with 12mL (4 ꢄ3 times) of ice-cold 50 mM Tris–HCl
buffer (pH 7.4) using a Brandel M-48R apparatus and
counted in 4 mL of Ultima Gold MV (Packard) in a
1204 Betaplate BS (Wallac) liquid scintillation spectro-
meter with counting efficiency about 60%. Dose–inhi-
bition curves were analysed by the ‘Allfit’ program to
obtain the concentration of unlabelled drugs that
inhibited ligand binding by the 50%.33 The Ki values
were derived from the IC50 values.34
13. Goetz, A. S.; King, H. K.; Ward, S. D. C.; True, T. A.;
Rimele, T. J.; Saussy, D. L., Jr. Eur. J. Pharmacol. 1995, 272,
R5.
14. Yocca, F. D.; Hyslop, D. K.; Smith, D. W.; Mayaan, S.
Eur. J. Pharmacol. 1987, 137, 293.
15. Orjales, A.; Alonso-Cires, L.; Labeaga, L.; Corcostegui,
R. J. Med. Chem. 1995, 38, 1273.
16. Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.;
Tortorella, V. Med. Chem. Res. 1999, 9, 340.
17. Modica, M.; Santagati, M.; Russo, F.; Parotti, L.; Sel-
vaggini, C.; Salmona, M.; Mennini, T. J. Med. Chem. 1997,
40, 574.
18. Modica, M.; Santagati, M.; Russo, F.; Selvaggini, C.;
Cagnotto, A.; Mennini, T. Eur. J. Med. Chem. 2000, 35, 677.
19. Skagerberg, B.; Bonelli, D.; Clementi, S.; Cruciani, G.;
Ebert, C. Quant. Struct.-Act. Relat 1989, 8, 32 .
20. Reid, J. R.; Heidel, N. D. J. Heterocycl. Chem. 1976, 13,
925.
21. Potts, K. T.; Huseby, R. M. J. Org. Chem. 1966, 31, 3528.
22. Eweiss, N. F.; Bahajaj, A. A.; Elsherbini, E. A. J. Het-
erocycl. Chem. 1986, 23, 1451.
Procedures involving animals and their care were con-
ducted in conformity with the institutional guidelines
that are in compliance with national (D.L. n. 116, G.U.,
suppl. 40, Feb. 18, 1992) and international laws and
policies (EEC Council Directive 86/609, OJ L 358, 1,
Dec. 12, 1987; Guide for the Care and Use of Labora-
tory Animals, US National Research Council, 1996).
23. van Wijngaarden, I.; Tulp, M. T.; Soudijn, W. Eur. J.
Pharmacol. 1990, 188, 301.
24. Lopez-Rodriguez, M. L.; Morcillo, M. J.; Rovat, T. K.;
Fernandez, E.; Vicente, B.; Sanz, A. M.; Hernandez, M.; Ore-
sanz, L. J. Med. Chem. 1999, 42, 36.
25. Lopez-Rodriguez, M. L.; Morcillo, M. J.; Fernandez, E.;
Porras, E.; Oresanz, L.; Beneytez, M. E.; Manzanares, J.;
Fuentes, J. A. J. Med. Chem. 2001, 44, 186.
Acknowledgements
The authors are grateful to the Italian M.U.R.S.T. for
financial support.
References and Notes
26. Bourdais, J. Bull. Soc. Chim. France 1968, 3246.
27. Bermann, M. C.; Bonte, J. P.; Lesieur-Demarquilly, I.;
Debaert, M.; Lesieur, D.; Leinot, M.; Benoit, J.; Labrid, C.
Eur. J. Med. Chem. 1982, 17, 85.
28. Yale, H. L.; Piala, J. J. J. Med. Chem. 1966, 9, 42 .
29. Hoggard, E. J. Chem. Soc 1949, 1918.
30. Richter, F., Ed. In Beilsteins Handbuch der Organischen
Chemie; Springer: Berlin, 1949; band 9, II, p 465.
31. Protons can be exchanged with D2O.
32. Caccia, S.; Confalonieri, S.; Guiso, G.; Bernasconi, P.;
Cagnotto, A.; Skorupscka, M.; Mennini, T. Psychopharma-
cology 1994, 115, 502.
1. Martin, G. R. In IUPHAR Compendium of Receptor
Characterization and Classification; IUPHAR Media, 1988; p
167.
2. Middlemiss, D. N.; Fozard, J. R. Eur. J. Pharmacol. 1983,
90, 151.
3. Fargin, A.; Raymond, J. R.; Lohse, M. J.; Kobilka, B. K.;
Caron, M. G.; Lefkowitz, R. J. Nature 1988, 335, 358.
4. Broekkamp, C. L. E.; Leysen, D.; Peeters, B. W. M. M.;
Pinder, R. M. J. Med. Chem. 1995, 38, 4615.
5. Blier, P.; Montigny, C. Trends Pharmacol. Sci. 1994, 15, 220.
6. Hamon, M. Trends Pharmacol. 1993, 112, 1.
7. Ramboz, S.; Oosting, R.; Amore, D. A.; Belzung, C.; Segu,
L.; Misslin, R.; Buhot, M. C.; Hen, R. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 14476.
33. De Lean, K. W.; Munson, P. J.; Rodbard, D. Am. J.
Physiol. 1978, 235, E97.
34. Cheng, Y.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22,
3099.