Synthesis and QSAR studies on hypotensive 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines

Article abstract of DOI:10.1016/j.bmcl.2006.12.072

A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are important

Full text of DOI:10.1016/j.bmcl.2006.12.072

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1708–1712
Synthesis and QSAR studies on hypotensive 1-[3-(4-substituted
phenylthio) propyl]-4-(substituted phenyl) piperazinesq
Anil K. Saxena,a,* Jyoti Rao,a Ruchika Chakrabarty,a Mridula Saxenaa and R. C. Srimalb
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
bDivision of Pharmacology, Central Drug Research Institute, Lucknow 226001, India
Received 18 September 2006; revised 11 December 2006; accepted 21 December 2006
Available online 23 December 2006
Abstract—A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated
for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are impor-
tant for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT2A receptor binding affinities
of these compounds suggests a possible role of 5-HT2A receptors in mediating the hypotensive action of title compounds.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Hypertension is a state of abnormally high pressure in
the arteries all the time. Between 85% and 90% of people
suffer from primary hypertension (with no known
cause), rest 10–15% of people have secondary hyperten-
sion (caused by renal, endocrine or pregnancy related
diseases). The disease is usually symptom less but if
untreated, it may result in heart enlargement and failure,
renal dysfunction and cerebrovascular accidents.
phenylthio) propyl]-4-(substituted phenyl) piperazines
and related compounds10–12 including 1-(aryl-pipera-
zin-1-yl)-1-oxo-2-(thioaryloxy/aryloxy) propanes13 have
been investigated for their hypotensive activity. Among
these compounds 1-[3-(4-acetamidophenylthio) propyl]-
4-[3-methyl phenyl] piperazine11 emerged as a potential
antihypertensive agent. It showed activity comparable
to centhaquin.14 The QSAR studies on a set of the ana-
logues of 1-[3-(4-acetamidophenylthio) propyl]-4-[3-
methyl phenyl] piperazine indicated that the variance in
activity is explained by the resonance and the hydropho-
bicity effects of the substituents on the phenyl rings.
Based on the above observations and in order to further
explore the effect of aromatic substitution on hypoten-
sive activity, another series of 1-[3-(4-substituted phenyl-
thio) propyl]-4-(substituted phenyl) piperazines was
synthesized and evaluated for their hypotensive activity
in vivo. In order to study the possible role of 5-HT2A
receptor affinity in the observed hypotensive activity in
these molecules, some selected compounds including
the least and most active ones were evaluated for their
affinities to 5-HT2A receptors. The quantitative struc-
ture–activity relationship (QSAR) studies have been car-
ried out to analyze the observed variance in hypotensive
activity in terms of the effect of physicochemical param-
eters (hydrophobic, steric and electronic) where the reso-
nance and hydrophobic parameters for the substituents
in the thioaryloxy and arylpiperazine part, respectively,
were found to be important for explaining the variance
in hypotensive activity and the former in 5-HT2A recep-
tor binding affinity. These studies are reported in this
paper.
Body mechanisms that control blood pressure are con-
trolled by the sympathetic division of the autonomic ner-
vous system and the kidneys. Drugs used, alone or in
combination, for treatment of hypertension are diuretics,
adrenergic blockers, centrally acting alpha-agonists,
angiotensin-converting enzyme (ACE) inhibitors, angio-
tensin II blockers, calcium channel blockers, direct vaso-
dilators and more recently 5-HT antagonists.1 One of the
important vascular effects of 5-HT is its ability to act as a
vasoconstrictor. The 5-HT2A, 5-HT2B and 5-HT1B recep-
tors have been implicated as mediators of 5-HT-induced
contraction in vascular smooth muscle. 5-HT2A recep-
tors mediate contraction in many arteries including the
rat thoracic aorta2 and pulmonary arteries3. In our earli-
er work, 1-(aryloxy/thioaryloxy)-3-(N-arylpiperazinyl)
propanes and propanols,4–9 series of 1-[3-(4-substituted
Keywords: Thioarylalkylpiperazines; Hypotensive; QSAR; 5-HT2A
binding affinity; Hydrophobicity; Resonance.
q
CDRI Communication No. 7077.
Corresponding author. Tel.: +91 522 2612411 18; fax: +91 522
2623405; e-mail: anilsak@gmail.com
*
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.072

A. K. Saxena et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1708–1712
1709
The 3-chloropropyl 4-substituted-phenyl sulfides were
prepared by the condensation of appropriate thiophe-
nols with 1-bromo-3-chloropropane in the presence of
sodium hydroxide in ethanol to give the key intermedi-
ate arylthiopropylchloride, which on condensation with
the corresponding substituted phenyl piperazines in dry
DMF in presence of sodium carbonate and sodium io-
dide afforded the desired compounds (1–34) in 70–85%
yields15 essentially according to our previously described
method11 (Scheme 1. and Table 1). All the compounds
have been characterized by IR, FAB-MS, NMR spec-
troscopic techniques and elemental analysis.
parameter regression analysis was carried out using SY-
STAT-7.1 software. Among different physicochemical
parameters viz. r (R0), r (R), R (R), F (R), p (R),
Rp(R0), [Rp (R0)]2 and MR (R) and MR (R0), the
parameters [Rp (R0)]2, MR (R) (r = 0.058) and p (R)
(r = 0.037) showed the least correlation with activity
while electronic
r
(R0) (r = ꢀ0.306),
r
(R)
(r = ꢀ0.158); resonance R (R) (r = ꢀ0.177), R (R0)
(r = 0.698); field effect F (R) (r = 0.140), F (R0)
(r = ꢀ0.485); hydrophobic Rp (R0) (r = 0.196) parame-
ters showed considerable correlation with activity.
Hence, different combinations of the independent
parameters were used for correlating the activity using
the classical Hansch regression analysis.
Hypotensive activity. The compounds were tested16 for
their effect on blood pressure in anaesthetized cats by
administration of 2 lmol/kg iv dose and the results are
given in Table 1. These compounds in general are good
hypotensive agents with % maximum blood pressure fall
ranging from 12.49 to 61.02. The compounds 1 and 2
show high profile of hypotensive activity in terms of fall
in blood pressure and longer duration of action. Two of
these (33 and 34) compounds showed tachyphylaxis and
one of them (33) with R = –NO2 is a positional isomer
of the compound 42 (Table 1) reported earlier.12
Although r (R0), F (R0) and R (R0) had good corre-
lations with hypotensive activity, but none of them
alone or in combination with the other parameters
could give statistically significant equation. Hence dif-
ferent sets of parameters viz. R (R), Rp (R0), [Rp
(R0)]2, with negligible intercorrelation between Rp
(R0) and R (R) (r = 0.1) and [Rp (R0)]2 and R (R)
(r = 0.03), were tried to derive equations where a com-
bination of R (R), Rp (R0) and [Rp (R0)]2 led to the
derivation of Eq. 1 where the figures in parentheses
describe the standard error of the regression coeffi-
cient, n represents the number of data points, r is
the correlation coefficient, s is the standard error from
the regression and F is the measure of statistical
5-HT2A receptor binding affinity. In vitro receptor bind-
ing studies for serotonergic 5-HT2A (rat striatal mem-
brane) were carried out17 (Table 2). The radioligand
and reference compound used for 5-HT2A receptor were
[3H] Ketanserin (60–90 Ci/mmol) and Ketanserin
(Ki = 0.4 nm), respectively.
significance of the regression model.
X
log C ¼ 0:599RðRÞðꢁ0:169Þ þ 1:933
pðR0Þðꢁ0:254Þ
X
2
ꢀ 1:175½
pðR0Þꢂ ðꢁ0:160Þ ꢀ 0:588ðꢁ0:077Þ
The QSAR studies have been carried out to find the
influence of physicochemical factors on the hypotensive
activity. In these studies the hypotensive activity was
taken as dependent and different physicochemical
parameters (hydrophobicity: p, electronic effect: r-Ham-
mett, resonance effect: R, field effect: F and steric effect:
MR) at positions R and R0 (Scheme 1) of the aromatic
rings as independent variables. In addition to the newly
synthesized 34 compounds (1–34), a set of 8 compounds
(35–42, taken from our earlier12 studies) showing >45%
fall in blood pressure were also considered for these
studies. Thus, a total set of 42 compounds was consid-
ered. Out of these compounds 3 compounds viz. 33, 34
from the newly synthesized set and 42 from earlier
reported compounds12 were not considered for QSAR
analysis as they showed tachyphylaxis. Thus, the
remaining 39 compounds were divided into a training
set of 28 compounds (1–22, 35–40) (Table 1) and a test
set containing 11 molecules (23–32, 4112) (Table 1).
The values for the physicochemical parameters were
computed and taken from the literature18 and the multi-
n ¼ 28; r ¼ 0:846; s ¼ 0:170; F ¼ 20:21
ð1Þ
Eq. 1 obtained above is statistically significant as it has
low standard error (0.170), moderate correlation coeffi-
cient (0.846) and high statistical significance
(F3,24a0.001 = 8.51; F3,24 = 20.21) with >99.9% values
for regression coefficients. It describes well the variation
in the observed hypotensive activity as shown by com-
parison of observed and calculated hypotensive activity
of these molecules (Table 1, Eq. 2, Fig. 1).
It is evident from the equation that resonance and
hydrophobic effects play an important role in the varia-
tion of activity. The resonance effect at position 4 of the
thioaryl ring positively contributes to the hypotensive
activity. Thus, substituents with positive values of reso-
nance parameter might show good activity. The relative-
ly poorer correlation of hypotensive activity with r and
Cl
(i)
(ii)
S
R
R'
+
HS
R
N
N
S
R
R'
Br
Cl
NH
N
1-34
Scheme 1. Reagents and condition: (i) NaOH, C2H5OH; (ii) dry DMF, Na2CO3, NaI, 75 ꢁC, 48 h.

1710
A. K. Saxena et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1708–1712
Table 1. Observed ‘%’ maximum blood pressure fall’ in anaesthetized cats induced by 34 derivatives of the general structure shown in Scheme 1
Compound R0
R
% Max. blood Duration (min) Mp (ꢁC)
logCe
Values of Hansch parameters
used
pressure fallc
(2 lmol/kg)
Found
Calcd/predf R (R)
Rp (R0) [Rp (R0)]2
1
2
2-CH3
3-Cl
CH3
H
OCH3
61.02
55.99
53.42
48.65
45.83
42.62
42.31
40.00
38.30
38.30
36.36
34.00
26.58
26.23
21.74
20.69
21.05
60
120
40
85
25
30
65
35
6
160
182
189a
Oil
83
0.1946
0.1046
0.0482
0.1922
ꢀ0.13
0.00
0.56
0.71
0.88
0.56
1.42
0.71
0.14
0.56
1.42
0.56
1.42
0.14
1.42
ꢀ0.02
0.14
0.14
1.42
1.42
0.14
0.14
0.14
0.3136
0.5041
0.7744
0.3136
2.0164
0.5041
0.0196
0.3136
2.0164
0.3136
2.0164
0.0196
2.0164
ꢀ0.0004
0.0196
0.0196
2.0164
2.0164
0.0196
0.0196
0.0196
ꢀ0.0004
ꢀ0.0004
0.0196
0.3136
0.0196
0.0000
ꢀ0.0004
0.0196
0.0196
0.3136
ꢀ0.0004
0.3136
0.0000
0.3136
0.3136
0.3136
0.3136
0.3136
0.3136
0.3136
0.3136
3
3-CF3
2-CH3
3,4-Di Cl
3-Cl
0.0595 ꢀ0.1025
ꢀ0.0235 ꢀ0.1795
ꢀ0.0726 ꢀ0.2125
ꢀ0.1291 ꢀ0.1135
ꢀ0.1347 ꢀ0.4300
ꢀ0.51
ꢀ0.51
0.00
4
NHC2H5
H
5
6
OCH3
Cl
Cl
Oil
95
ꢀ0.51
ꢀ0.15
ꢀ0.15
ꢀ0.34
ꢀ0.34
ꢀ0.13
ꢀ0.34
ꢀ0.15
0.00
7
4-F
8
2-CH3
3,4-Di Cl
3-CH3
148
Oil
Oil
Oil
184a
180
Oil
76
ꢀ0.1761
0.0362
9
F
ꢀ0.2071 ꢀ0.4163
ꢀ0.2071 ꢀ0.0776
ꢀ0.2431 ꢀ0.2904
ꢀ0.2880 ꢀ0.5439
ꢀ0.4413 ꢀ0.3024
ꢀ0.4490 ꢀ0.6258
ꢀ0.5563 ꢀ0.4180
ꢀ0.5835 ꢀ0.3401
ꢀ0.5741 ꢀ0.5182
ꢀ0.6021 ꢀ0.3683
ꢀ0.6059 ꢀ0.4420
ꢀ0.6747 ꢀ0.6458
ꢀ0.6880 ꢀ0.6458
ꢀ0.7404 ꢀ0.6258
ꢀ0.8452 ꢀ0.8299
ꢀ0.5843 ꢀ0.5441
ꢀ0.1556 ꢀ0.1795
ꢀ0.5699 ꢀ0.4964
ꢀ0.7783 ꢀ0.7917
ꢀ0.5600 ꢀ0.7280
ꢀ0.8063 ꢀ0.7477
ꢀ0.4572 ꢀ0.2446
ꢀ0.2200 ꢀ0.0777
ꢀ0.5233 ꢀ0.7280
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24d
25d
26d
27d
28d
29d
30d
31d
32d
33b
34b
35
36
37
38
39
40
41d
42b
F
65
10
60
90
90
35
50
11
30
3,4-Di Cl CH3
3-F
3,4-Di Cl Cl
F
2-OCH3
4-F
4-F
H
CH3
H
ꢀ0.13
0.00
107
Oil
132
97
3,4-Di Cl OCH3
3,4-Di Cl NHCOCH3 20.00
ꢀ0.51
ꢀ0.26
ꢀ0.17
ꢀ0.51
ꢀ0.51
4-F
4-F
Br
OCH3
19.86
17.46
17.02
15.38
12.49
20.66
41.14
0.30
0.30
30
202
152
95
3-F
OCH3
H
4-OCH3
4-OCH3
4-F
30
60
0.000 ꢀ0.02
F
97
91
ꢀ0.34
ꢀ0.02
0.14
0.56
0.14
0.00
ꢀ0.02
0.14
0.14
0.56
ꢀ0.02
0.56
0.00
0.56
0.56
0.56
0.56
0.56
0.56
0.56
0.56
F
NHC2H5
90
10
ꢀ0.34
ꢀ0.51
ꢀ0.26
ꢀ0.34
ꢀ0.17
ꢀ0.68
0.16
3-CH3
4-F
Oil
138
75
NHCOCH3 21.21
17
50
H
F
Br
14.28
21.59
13.51
25.87
37.59
23.06
42.00
41.07
2-OCH3
4-F
4-F
15
30
85
68
NH2
NO2
F
60
30
70
40
2-CH3
4-OCH3
2-CH3
H
ꢀ0.34
ꢀ0.17
0.16
Br
40
30
114
147
60
NO2
H
0.7241
0.6969
—
—
30
0.00
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
2-CH3
3-CH3
3-CH3
NHCOCH3 55.0
>180
47
84
Oil
148
160
Oil
Oil
180
147
190
0.0871 ꢀ0.0297
ꢀ0.26
ꢀ0.68
ꢀ0.13
0.00
NH2
CH3
H
24.28
55.74
65.15
43.80
ꢀ0.4939 ꢀ0.2814
0.1002
0.2717
0.04820
0.1261
0.03621
>86
92
Cl
ꢀ0.1082
ꢀ0.15
0.26
NHCOCH3 51.61
OCH3
NO2
60
52
0.0279 ꢀ0.0297
21.4
84.41
ꢀ0.5649 ꢀ0.1795
ꢀ0.51
0.16
120
0.7335
—
a HCl salt.
b Compound showed tachyphylaxis.
c Each entry is mean of three experimentally determined values.
d Compounds included in the test set.
e Where C = % fall in BP/(100 ꢀ % fall in BP).
f Calcd (calculated for training set), pred (Predicted for test set).
F than R suggests that the phenyl ring containing the
substituents R does not inhibit the conjugation between
the p-electron clouds of the phenyl ring and the lone pair
of the thio group and thus the major electronic effect is
through resonance. It is interesting to note that the value
of intercorrelation between the r and R parameters in
our earlier study12 was 0.923 and hence it was difficult
to decide between the role of R and r for hypotensive
activity while in this set of compounds with nonorthog-
onal relation of R and r (r = 0.077) it is clear that the
major contribution towards activity is through the reso-
nance effect of the R substituents. The parabolic rela-
tionship between hypotensive activity and the
hydrophobicity indicate the optimum hydrophobicity
value for the substituent is [p (R0)]0 = 0.823 and that
the transport of the drug to the active site is the rate-lim-
iting step for hypotensive activity which is well expected
as the hypotensive activity was measured in the whole
animal system. These results also corroborate our earlier
results where the similar dependence of hypotensive
activity on resonance and hydrophobicity (in terms of
molecular lipophilicity potentials) was observed.12 The
validity of the derived model was further tested on 11
molecules of the test set (indicated by
in Table 1)
*

A. K. Saxena et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1708–1712
1711
Table 2. 5-HT2A receptor binding affinity studies on selected
compounds
considered for regression analysis in combination with
R (R), p (R0), R (R0).
Compound % inhibition Kia
p (R)
logAb at 10ꢀ6 M
Found Calcd
at 10ꢀ6 Ma
(nm)
Combination of p (R) and R (R0), p (R0) and R (R), p
(R0) and R (R0) gave moderate values for correlation
coefficient (r = 0.787, 0.788, 0.784, respectively), and
also the regression coefficients with the independent
parameters were statistically not significant (<90%).
23
24
26
27
32
34
35
38
40
42
25.70
32.90
85.40
37.0
nd
nd
nd
nd
nd
nd
0.14 ꢀ0.4610 ꢀ0.2059
0.14 ꢀ0.3095 ꢀ0.2059
ꢀ0.97
0.7671
0.7268
0.14 ꢀ0.2311 ꢀ0.2059
0.86 ꢀ0.2293 ꢀ0.5856
37.10
37.40
94.7
The variation in 5-HT2A binding affinities in this set of
compounds was best described by the following Eq. 2
where a negligible intercorrelation between Rp (R) and
R (R) (r = 0.08) was observed.
0.0
ꢀ0.2237
1.2521
0.4907
0.4243
0.6144
0.2466
0.7268
0.2466
0.7268
0.6238
6.09 ꢀ0.97
75.58
72.65
80.45
13.6
0.0
21.1
21.1
ꢀ0.97
ꢀ0.28
log C ¼ 1:015RðRÞðꢁ0:666Þ þ 0:767pðRÞðꢁ0:192Þ
þ 0:247ðꢁ0:165Þ n ¼ 10; r ¼ 0:845;
a Values are means of two experiments, (nd, not done).
b Where A = % inhibition/(100 ꢀ % inhibition).
s ¼ 0:34; F ¼ 8:72
ð4Þ
0.3
0.2
0.1
Eq.
2
with good correlation coefficient value
(r = 0.845), low standard error (s = 0.34) and good
statistical significance (F2,7a0.01 = 7.55; F2,7 = 8.72, with
>99.9% values for regression coefficients) well
describes the variance in 5-HT2A affinity as shown
by the good match between observed and calculated
log Affinity values (Fig. 3, Eq. 5. The dependence of
hypotensive activity as well as 5-HT2A receptor bind-
ing affinity positively on resonance parameter of the
substituents of the thioaryl ring suggests that the
5-HT2A receptors may be involved in mediating the
hypotensive action of these compounds. The parabolic
dependence of hypotensive activity on hydrophobicity
of R0 substituents suggests that the rate limiting factor
in the hypotensive action is the transport of the mol-
ecule at the active site which overweighs the role of
hydrophobicity in the thioaryl part of the molecule
for binding. It may be the reason for insignificant con-
tribution of hydrophobicity of R substituents in the
hypotensive activity while statistically significant nega-
tive contribution for binding affinity. These studies
also support our earlier proposition12 that the thioaryl
part in these molecules is more important for binding
at the receptor and the rest of the molecule is
responsible for the transport of the molecule to the
receptor site.
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
Log Activity (Found)
Figure 1. log Act:Calcd ¼ 0:716 log Act:Foundðꢁ0:88Þ ꢀ 0:072ðꢁ0:035Þ
n ¼ 28; r ¼ 0:846; s ¼ 0:138; F ¼ 65:66: ð2Þ
where a good match between the observed and predicted
hypotensive activity has been obtained (Fig. 2, Eq. 3).
As 10 of these compounds were studied for their 5-HT2A
binding affinities it appeared of interest to develop
QSAR in these compounds. Among all the parameters
considered, only p (R) (r = ꢀ0.787), p (R0) (r = 0.784),
MR(R) (r = 0.709), F (R0) (r = ꢀ0.336) and R (R)
(r = 0.244), R (R0) (r = 0.304) showed considerable cor-
relation with biological activity. Among these MR(R)
was highly correlated with p (R) (r = ꢀ0.70), and p
(R) had a better correlation with log Affinity than MR
(R) (r = 0.709) hence out of these two only p (R) was
1.5
1
0
-0.2
-0.4
-0.6
-0.8
-1
0.5
0
-0.5
-1
-1
-0.8
-0.6
-0.4
-0.2
0
-1
-0.5
0
0.5
1
1.5
Log Activity (Found)
Log Affinity (found)
Figure 2. log Act:Calcd ¼ 0:629 log Act:Foundðꢁ0:148Þ ꢀ ðꢁ0:085Þ n ¼
11; r ¼ 0:817; s ¼ 0:133; F ¼ 18:06: ð3Þ
Figure 3. log Aff:Calcd ¼ 0:714 log AffFoundðꢁ0:160Þ þ 0:060ðꢁ0:093Þ
n ¼ 10; r ¼ 0:845; s ¼ 0:27; F ¼ 19:94: ð5Þ

1712
A. K. Saxena et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1708–1712
General Procedure: preparation of compound 10: a
Acknowledgments
mixture of 1-(3-methylphenyl) piperazine (0.352 g,
2 mmol), 1-[3-(4-fluorophenylthio) propylchloride (pre-
pared according to literature method1) (0.429 g, 2.1 mmol)
and sodium carbonate (0.22 g, 2.1 mmol), sodium iodide
(0.002 g, 0.1 mmol) in dry dimethylformamide (2 mL) was
stirred at 75 ꢁC for 48 h. The reaction mixture was cooled
and then poured into water. The separated solid was
filtered and crystallized from ethanol–water to give 1-[3-
(4-fluorophenylthio) propyl]-4-(methoxy-phenyl) pipera-
zine. Yield: 0.60 g, 87.2%. FABMS m/z: 344 [M+]. IR
(KBr, cmꢀ1): 2900, 1520, 1500, 1445, 1230, 940, 840, 720.
1H NMR (CDCl3, 90 MHz): d 1.4–1.9 (m, 2H), 2.2 (s, 3H),
2.3–2.8 (m, 8H), 2.9–3.2 (m, 4H), 6.4–6.7 (m, 6H), 6.9–7.2
(m, 2H). Anal. Calcd for C20H25FN2S (344.17): C, 69.73;
H, 7.31; N, 8.13. Found: C, 70.44; H, 6.99; N, 8.0.
Authors are thankful to Messrs Z. Ali and A. S. Kush-
waha for their excellent technical assistance; RSIC, Luc-
know, for providing spectroscopic data and NIDA &
NOVA Screen USA, for providing receptor binding
data. One of the authors RC is thankful to CSIR, India,
for the award of senior research fellowship.
References and notes
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15. Experimental: All melting points were determined in an
electrically heated apparatus (Tempo and Toshniwal) and
are uncorrected. The IR spectra were recorded on Perkin-
Elmer 137 spectrophotometers. Mass spectra were record-
ed on a JEOL SX 102/DA-6000 spectrometer. NMR
spectra were recorded on Varian R-32 (90 MHz) instru-
ments using tetramethylsilane as internal standard.
Elemental analyses (C, H, N) of the synthesized com-
pounds were found to be 0.45 of the theoretical values.