X. Wang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1729–1732
1731
Table 2. The biological activities of compounds 6a–f Table 4. The biological activities of compounds 10d, 18, 19 and 6d
Compd
n
Dose
Sedative
Analgesic
Death dose
(mg/kg sc) activitya (%)b activitya (%)c (mg/kg sc)
6a
6b
6c
6d
6e
6f
1
22
3
4
5
2
0
47.7
0
40
0
00
70.4
0
0
2
267.4
0.28.1
0.020
2
2
0.2
6 7.5 0.022
0
0.2
a,b,c
As defined in Table 1.
Table 3. The biological activities of compounds 17a–d
Compd
n
Dose
(mg/kg sc)
Analgesic
activitya (%)c
17a
1
2
0
90
10
5
20
10
5
2.5
20
20
46
34
100
91
61
49
18
24
Compd
Dose (mg/kg sc)
Analgesic activitya (%)c
17b
5
6d
18
10d
19
0.270.4
10
5
10.9
34.5
60.1
17c
17d
11
17
0.05
a,cAs defined in Table 1.
a,c
As defined in Table 1.
As shown in Table 3, the introduction of suitable lipophilic
group was favorable to improve the analgesic activity.
Thus, compounds 17a and 17b exhibited good analgesic
activity and dose–effect relationship, however, the anal-
gesic activity of compounds 17c and 17d was very weak.
analgesic activity, compound 10d, the hexanedioyl bi(4-
methyl-1-piperazine) dihydrochloride 18 and the hex-
anedioyl bi(4,4-dimethyl-1-piperazine) dibromide 19
were also tested for their analgesic activity (Table 4).
It could be found from Table 4 that the secondary amine
hydrochloride 10d and tertiary amine hydrochloride 18
only exhibited weak analgesic activity; however, the
quaternary ammoniums 19 and 6d showed higher activ-
ity. This result demonstrates that the quaternary
ammonium functionality is a critical pharmacophore
for the analgesics.
Results and Discussion
Most of the compounds tested displayed definite
analgesic or sedative activity. The results reported in
Table 1 clearly show that the distance between two
spirocyclopiperaziniums obviously affected the biologi-
cal activities. The analgesic activity increases as n
decreases, and the sedative activity increases as n
increases. Thus, analgesic activity and sedative activity
of compound 5a (n=3) is 96 and 4.7% separately at the
dose of 10 mg/kg sc. On the contrary, compound 5c
(n=8) exhibited high sedative activity (98.6%) and no
analgesic activity at the dose of 0.2mg/kg sc.
In summary, three series of dispirocyclopiperazinium
salts synthesized in this study showed analgesic and/or
sedative effects, especially, compounds 5a, 17a and 17b
which processed excellent analgesic activity. Two
important structure–activity relationships were observed
from this study: (1) the quaternary ammonium func-
tionality is a critical pharmacophore for the analgesics;
(2) it is important to adjust the lipophilic properties of
compounds for the improvement of analgesic activity.
When two spirocyclopiperazinium cations were linked
with a,o-diacyl in a series of compounds 6, only com-
pound 6d (n=4) was found to show significant analgesic
activity (70.4%, dose 0.2mg/kg), and the others did not
show analgesic activity and various sedative activity
(Table 2). The death doses of derivatives 6a–f were also
tested. It is apparent from the results that the toxicity
was raised with the increase of n.
Acknowledgements
This research was supported by the funds of National
Science Foundation of China (NSFC 29972005). Bio-
logical activities were completed by National Center for
Drug Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences.
Compared with the analgesic activity of compounds 5a–
d and 6a–f, compound 5a is the most potent lead. In
order to improve the ability to across the blood–brain
barrier (BBB), a new class of 5a analogue, 17a–d, in
which a different length of carbon chain was introduced
into compound 5a through an ether bond, was designed
and synthesized. The data of analgesic activity were lis-
ted in Table 3.
References and Notes
1. Kizawa, Y.; Takayanagi, I. Gen. Pharmacol. 1984, 15, 149.
2. Lippiello, P. M.; Fernandes, K. G. Mol. Pharmacol. 1986,
29, 448.