Chemistry Reference
In-Depth Information
A
B
C
pH 5
activation
Heat
activation
Capsaicin
activation
125
100
100
100
80
80
75
60
60
50
40
40
25
20
20
0
0
0
-10
-9
-8
-7
-6
-10
-9
-8
-7
-6
-10
-9
-8
-7
-6
Compound 44 [log M]
Compound 44 [log M]
Compound 44 [log M]
Figure 13.20
Effects of compound 44 on capsaicin (0.5 mM), pH 5, and heat (45 1C)
activation of human TRPV1 (A to C); each point in the graph is an
average
S.D. of an experiment conducted in triplicate. Note that
compound 44 blocked pH 5 activation partially and capsaicin and heat
activation fully, making it a ''profile B'' compound at the human
receptor. Reproduced with permission of the American Society for
Pharmacology and Experimental Therapeutics from J. Pharmacol. Exp.
Ther., 2008, 326, 218.
through the introduction of ring saturation and the incorporation of basic
groups in this series of TRPV1 antagonists.
In addition to the identification of the two clinical candidates, subsequent
efforts to better understand TRPV1 antagonist-induced hyperthermia lead to
greater insights of the role of this channel in body-temperature maintenance.
We found that peripheral restriction alone was not sucient to eliminate
TRPV1 antagonist-induced hyperthermia, suggesting that the site of action is
predominantly peripherally mediated. Additional investigations with modality-
specific TRPV1 antagonists also provided intriguing results. These studies led
to the identification of a unique ''profile C'' type of TRPV1 modulator that
blocks capsaicin activation, potentiates pH 5 activation, and does not impact
heat activation while lacking the hyperthermia liability.
The recent results of TRPV1-induced hyperthermia reported by our
laboratory and others have triggered a surge of interest in the role of TRPV1 in
thermoregulation.
78,79
For example, Romanovsky et al. have critically dissected
the thermoregulatory responses of TRPV1 agonist and antagonists and pro-
pose differential effects on two principal neuronal populations.
80
Studies such
as these continue to increase our understanding of how TRPV1 functions in
thermoregulation and help biologists gain further insights into the pharmaco-
logical role of this complex channel. As these preclinical studies continue,
several other companies are also evaluating TRPV1 antagonists in the clinic
(e.g., AZD1386, GRC 6211, JTS 653, MK 2295, and SB-705498). Recent
information from conference presentations and the clinical trial website, clin-
icaltials.gov, indicate that several of these trials have been completed, termi-
nated, or suspended. Results from these clinical studies should provide valuable
information about TRPV1 pharmacology and ultimately help afford resolution
on the potential therapeutic utility of TRPV1 antagonists.
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