Chemistry Reference
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Capsaicin
pH 5
Heat
Profile A
125
125
125
100
100
100
NHAc
F
3
C
75
75
75
N
S
50
O
50
50
25
25
N
BocHN
N
25
0
0
0
42
-11 -10 -9
-8
-7
-6
-11 -10 -9 -8 -7 -6
Cmpd 42 [log M]
-11 -10 -9 -8 -7 -6
Cmpd 42 [log M]
Cmpd 42 [log M]
Profile B
125
125
125
100
OH
100
100
F
3
C
75
75
N
75
50
50
50
N
O
25
25
25
0
0
0
43
-10 -9 -8 -7 -6 -5
Cmpd 43 [log M]
-10 -9 -8 -7 -6 -5
Cmpd 43 [log M]
-10 -9
-8
-7
-6
-5
Cmpd 43 [log M]
Profile C
150
125
200
175
150
125
OH
125
F
3
C
100
N
100
75
100
75
50
75
N
O
50
50
25
25
25
0
0
0
44
-11-10 -9 -8 -7
-6
-5
-11-10 -9 -8 -7
-6
-5
-11-10 -9 -8 -7
-6
-5
Cmpd 44 [log M]
Cmpd 44 [log M]
Cmpd 44 [log M]
Profile D
300
300
125
F
3
C
250
200
150
250
200
150
100
N
N
S
75
NH
NN
50
N
100
100
25
50
50
0
0
0
45
-10 -9
-8
-7
-6
-5
-10 -9
-8
-7
-6
-5
-10 -9
-8
-7
-6
-5
Cmpd 45 [log M]
Cmpd 45 [log M]
Cmpd 45 [log M]
Figure 13.17
Characterization of in vitro profiles of TRPV1 modulators 42-45.
Effects on capsaicin (0.5 mM), pH 5, and heat (45 1C) activation of rat
TRPV1. Profiles A-D: each point in the graph is an average
รพ
SD of an
experiment conducted in triplicate. Reproduced with permission of the
American Society for Pharmacology and Experimental Therapeutics
from J. Pharmacol. Exp. Ther., 2008, 326, 218.
respectively) produced a significant 1.0-1.5 1C increase in body temperature
(data not shown), while compound 44 (profile C) did not cause hyper-
thermia and, in fact, a modest decrease in temperature (
0.6 1C) was observed
(Figure 13.18A). Interestingly, compound 45 (profile D), which potentiated
both heat and pH 5, caused a marked hypothermic response (
2.9 1C)
(Figure 13.18B).
With the identification of a selective modulator of rodent TRPV1 that did
not cause hyperthermia, we evaluated compound 44 in a biochemical challenge
model (capsaicin-induced flinch), and three pain models: CFA- and surgical
incision-induced thermal hyperalgesia in rats, and acetic-acid induced writhing
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