942
S.-W. Lin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 940–943
Table 1
The analgesic activities of compounds 14a–14v assessed by acetic acid writhing test
R2
N
N+ X-
R3
R1
14a-v
Compd
R1
HNR2R3
X
Analgesic activitiesa,b,c (%)
14a
14b
14c
14d
14e
14f
14g
14h
14i
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
H
Dimethylamine
Dibutylamine
N-Methylbenzylamine
Pyrrolidine
Piperidine
Hexamethyleneimine
Morpholine
2,6-Dimethyl morpholine
Piperazine
1-Methylpiperazine
1-(2-Phenylethyl)piperazine
1-(4-Methoxyphenyl) piperazine
1-Benzoyl piperazine
Indoline
Indoline
Indoline
Indoline
Indoline
Indoline
Indoline
Indoline
Indoline
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
56
54
43
41
26
28
41
21
5
32
27
17
50
63
28
54
39
37
34
39
44
39
14j
14k
14l
14m
14n
14o
14p
14q
14r
14s
14t
14u
14v
4-NO2
3-NO2
3-CH3O
3-OH
3-AcNH
2-Cl
MsO
MsO
Cl
Cl
Cl
Cl
Cl
2-CH3O
a
Drugs were dissolved in isotonic saline solution (NaCl 0.9%) immediately before use. Drug concentrations were prepared in such a way that the
necessary dose could be administered in a volume of 10 mL/kg. Mice were administered with drugs (20 mol/kg, sc) 30 min prior to injection of 0.6% acetic
l
acid (10 mL/kg, ip). The number of stretching movements was recorded for 10 min, starting 5 min after acetic acid injection.
b
Percent analgesia was expressed by following formula: % Inhibition = 100 ꢀ (A/B ꢁ 100), where A = incidence of writhing in the treated group and
B = incidence of writhing in the control group.
c
P <0.05.
compounds 14k and 14l were synthesized. The results revealed
that a large substituent at the 4-position of the six-member
NR2R3 ring is not preferred. However, 14m with 1-benzoyl pipera-
zine for NR2R3 exhibited 50% analgesic activity. Since the C@O
bond is sp2 hybridized, 14m may have a special conformation to
bind to the receptor. Inspired by this result, we introduced indoline
and obtained a rather good result of 63% analgesic activity (14n,
63%). The results of 14m and 14n hint us that a phenyl ring at a
proper position of NR2R3 was preferred, which might contribute
which might be beneficial to expose the cationic nitrogen to bind
to the receptor, and possibly interact with the receptor via
p-p
interaction; introduction of substituting group on the N4-phenyl
ring could improve the activity, and the best position was the 4-po-
sition. More importantly, compound 14n with a new kind of mono-
spirocyclopiperazinium salt was identified to show potent
analgesic activity, which would be very valuable for the further
investigation of this program.
to affinity with a suitable conformation and/or
p–p
interaction.
Acknowledgments
Furthermore, we explored the influence of the substituted
groups of the N4-aromatic ring on analgesic activity. Compared to
compound 14o (28%) without any substituted group, both elec-
tron-donating group (14n, 4-CH3O, 63%) and electron-withdrawing
group (14p, 4-NO2, 54%) at the 4-position were beneficial for the
analgesic activity, while similar substituted groups at the 3-posi-
tion afforded only slight enhancement in activity (14r, 3-CH3O,
37%; 14q, 3-NO2, 39%). In addition, groups such as 3-OH (14s,
34%) and 3-AcNH (14t, 39%), which are both H-bond donors and
acceptors, did not further improve the analgesic activity. Consider-
ing the special conformation of the spirocyclopiperazinium struc-
ture, substituted groups at the 4-position of the N4-aromatic ring
might bind more tightly to the receptor than those at the 3-posi-
tion. Furthermore, compounds 14u and 14v were also a little more
effective than 14o. This result is opposite to traditional agonists,
whose substituents at the 2-position weaken the activity signifi-
cantly. It may confirm the effect of the special spirocyclopiperazi-
nium conformation.
This research was supported by the fund of National Science
Foundation of China (NSFC 20372006). Biological activities were
completed by Department of Molecular and Cellular Pharmacol-
ogy, School of Pharmaceutical Sciences, Peking University.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. Decker, M. W.; Meyer, M. D. Biochem. Pharmacol. 1999, 58, 917.
2. Kowaluk, E. A.; Lynch, K. J.; Jarvis, M. F. Annu. Rep. Med. Chem. 2000, 35, 21.
3. Jones, P. G.; Dunlop, J. Neuropharmacology 2007, 53, 197.
4. (a) Donnelly-Roberts, D. L.; Puttfarcken, P. S.; Kuntzweiler, T. A.; Briggs, C. A.;
Anderson, D. J.; Campbell, J. E.; Piattoni-Kaplan, M.; McKenna, D. G.; Wasicak, J.
T.; Holladay, M. W.; Williams, M.; Arneric, S. P. J. Pharmacol. Exp. Ther. 1998,
285, 777; (b) Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.;
Donnelley-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson, A. H.;
Porsolt, R. D.; Williams, M.; Arneric, S. P. Science 1998, 279, 77; (c) Holladay, M.
W.; Wasicak, J. T.; Lin, N. H.; He, Y.; Ryther, K. B.; Bannon, A. W.; Buckley, M. J.;
Kim, D. J.; Decker, M. W.; Anderson, D. J.; Campbell, J. E.; Kuntzweiler, T. A.;
Donnelly-Roberts, D. L.; Piattoni-Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric,
S. P. J. Med. Chem. 1998, 41, 407; (d) Ji, J. G.; Bunnelle, W. H.; Anderson, D. J.;
In summary, selecting monospirocyclopiperazinium salt 9b as
the lead compound, a series of monospirocyclopiperazinium salts
were designed and synthesized to search for a peripherally-acting
analgesic drug with low side effects. Extensive SAR studies re-
vealed that a suitable NR2R3 was critical for the analgesic activity,