Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats.
Antagonists of the vanilloid receptor TRPV1 (transient receptor potential vanilloid type 1) have been reported to produce antihyperalgesic effects in animal models of pain. These antagonists, however, also caused concomitant hyperthermia in rodents, dogs, monkeys, and humans. Antagonist-induced hyperthermia was not observed in TRPV1 knockout mice, suggesting that the hyperthermic effect is exclusively mediated through TRPV1. Since antagonist-induced hyperthermia is considered a hurdle for developing TRPV1 antagonists as therapeutics, we investigated the possibility of eliminating hyperthermia while maintaining antihyperalgesia. Here, we report four potent and selective TRPV1 modulators with unique in vitro pharmacology profiles (profiles A through D) and their respective effects on body temperature. We found that profile C modulator, (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide (AMG8562), blocks capsaicin activation of TRPV1, does not affect heat activation of TRPV1, potentiates pH 5 activation of TRPV1 in vitro, and does not cause hyperthermia in vivo in rats. We further profiled AMG8562 in an on-target (agonist) challenge model, rodent pain models, and tested for its side effects. We show that AMG8562 significantly blocks capsaicin-induced flinching behavior, produces statistically significant efficacy in complete Freund's adjuvant- and skin incision-induced thermal hyperalgesia, and acetic acid-induced writhing models, with no profound effects on locomotor activity. Based on the data shown here, we conclude that it is feasible to modulate TRPV1 in a manner that does not cause hyperthermia while maintaining efficacy in rodent pain models.
Lehto
Sonya G
SG
Department of Neuroscience, One Amgen Center Dr., Thousand Oaks, CA 91320-1799, USA.
Tamir
Rami
R
Deng
Hong
H
Klionsky
Lana
L
Kuang
Rongzhen
R
Le
April
A
Lee
Doo
D
Louis
Jean-Claude
JC
Magal
Ella
E
Manning
Barton H
BH
Rubino
John
J
Surapaneni
Sekhar
S
Tamayo
Nuria
N
Wang
Tingrong
T
Wang
Judy
J
Wang
Jue
J
Wang
Weiya
W
Youngblood
Brad
B
Zhang
Maosheng
M
Zhu
Dawn
D
Norman
Mark H
MH
Gavva
Narender R
NR
D000178:Acrylamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*
C530362:(R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide; D000178:Acrylamides; D000700:Analgesics; D010880:Piperidines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat