Table 3. In vitro hTRPV1 antagonistic activities for the C-region analogues
of 6
that antagonist 6 blocked the hypothermic effect of capsaicin in
vivo, consistent with its in vitro mechanism, and showed
promising analgesic activity in the formalin mouse pain model.
Acknowledgments
Ra
Ki[CAP] (nM)
This research was suppported by research grants from
Grünenthal in Germany and by Bio & Medical Technology
Development Program of the National Research Foundation
(NRF) funded by the Ministry of Science, ICT & Future
Planning (NRF-2016M3A9B5939892).
6
0.2
22
23
0.9 (±0.17)
0.8 (±0.12)
References and Notes
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24
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Consistent with its in vitro mechanism of action, it was able
to block in vivo the acute hypothermic response to capsaicin (3
mg/kg) injected intraperitoneally (ip). The oral administration
(po) of 3 and 10 mg/kg 6 antagonized the effect of capsaicin on
body temperature with 57% and 100% inhibition, respectively,
of the hypothermia induced by capsaicin. The in vivo analgesic
activity of 6 was evaluated employing the formalin test24 in mice
(Table 4). It demonstrated a reasonable antinociceptive effect in
the second period (20–30 min after injection), with 43%
inhibition of response at the dose of 3 mg/kg by intravenous
injection (iv). However, it showed hyperthermia at 10 mg/kg po
as side effect probably due to strong antagonism to all activators
as shown in Table 4.9
Table 4. Antagonistic activities of 6 for multiple activators in hTRPV1 and
rTRPV1.
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Activators, parameter
6
hTRPV1
CAP (f)Ki (nM)
pH, IC50 (nM)
heat 45oC, IC50 (nM)
rTRPV1
CAP (f)Ki (nM)
Anti-hypothermiaa
0.2
8.7
8.1
0.1
57% (3 mg/kg, po)
100% (10 mg/kg, po)
43% (3 mg/kg, iv)
Formalin test
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a Inhibition percent to hypothermic response by 3 mg/kg ip capsaicin
In summary, a series of 3-fluoro-4-methylsufonamidophenyl
A-region analogues of potent antagonist 1 were investigated. The
analysis of SAR indicated that a fluoro group at the 3- (or/and)
5-position and a 4-methylsulfonamido group at the 4-position
were optimal for TRPV1 antagonism to capsaicin activation, and
any modification in the A-region led to a reduction in
antagonism except for incorporation of an additional fluoro
group into the 5-position. The most potent antagonist 6 exhibited
potent antagonism toward capsaicin, low pH and elevated
temperature for hTRPV1 and also displayed highly potent
antagonism to capsaicin for rTRPV1. Further studies indicated
12. Ha T-H, Ryu H, Ki, S-E, Kim HS, Ann J, Tran P-T, Hoang
V-H, Son K, Cui M, Choi S, Blumberg PM, Frank R, Bahrenberg
G, Schiene K, Christoph T, Frormann S, Lee J. Bioorg
Med Chem. 2013;21:6657.
13. Ryu H, Seo S, Cho S-H, Kim HS, Jung A, Kang DW, Son K,
Cui M, Hong S-h, Sharma PK, Choi S, Blumberg PM, Frank-
Foltyn R, Bahrenberg G, Stockhausen H, Schiene K, Christoph,
T, Frormann S, Lee J. Bioorg Med Chem Lett. 2014;24:4039.
14. Ryu H, Seo S, Cho S-H, Kim MS, Kim M-Y, Kim HS, Ann
J, Tran P-T, Hoang V-H, Byun J, Cui M, Son K, Sharma PK,