Chemistry Reference
In-Depth Information
A
B
1.5
100
80
1.0
60
40
0.5
20
0
0.0
37
38
39
40
41
37
38
39
40
41
Compound Number
Compound Number
Figure 13.16
(A) Inhibition of capsaicin-induced flinching. Compounds dosed orally
at 1mg kg
1
(37, 40), 3mg kg
1
(39), or 10mg kg
1
(38, 41)in5%
Tween 80/Oralplus 1 h prior to capsaicin challenge in male Sprague
Dawley rats. (B) Effect of TRPV1 antagonists on body core tempera-
ture. Compounds dosed orally at 1mg kg
1
(37, 40),3mgkg
1
(39), or
10mg kg
1
(38, 41) in 5% Tween 80/Oralplus to male Sprague Dawley
rats implanted with radiotelemetry probes. Body core temperature
baselines were recorded 30 min before dosing, and temperature
recordings were continued for 2 h. The histogram shows body core
temperatures at 60 min post-drug administration. Adapted with per-
mission of the American Chemical Society from J. Med. Chem., 2008,
51, 2744.
other stimuli, we postulated that compounds with alternative profiles
(depending on how the channel is activated) may also provide different phar-
macological responses. To identify such compounds we mined our database
and examined TRPV1 activities against rat capsaicin, pH 5, and heat. From
this analysis we identified compounds with four distinct rat TRPV1 modulation
profiles (Figure 13.17). Compound 42 (profile A) blocked all modes of acti-
vation (similar to AMG 517); compound 43 (profile B) blocked capsaicin and
heat but not proton activation; compound 44 (profile C) blocked capsaicin but
not heat activation and potentiated pH5 activation; and compound 45 (profile
D) blocked capsaicin activation and potentiated both heat and pH 5 activation
of TRPV1. It should be noted that both compounds 44 and 45 by themselves
did not induce
45
Ca
21
uptake into CHO cells expressing the rat TRPV1
channels at physiological pH (pH7.2), indicating that they are not partial
agonists. In addition to blocking capsaicin activation, all four compounds
inhibited putative endogenous ligand (AEA and NADA) activation of TRPV1
(data not shown).
To evaluate the effect of the four unique TRPV1 modulation profiles in vivo,
compounds 42-44 were administered to rats implanted with radiotelemetry
probes to monitor body temperature. The effects of the different profiles on
thermal regulation were striking. Both 42 and 43 (profiles A and B,
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