title: 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.
abstract: 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.
authors.affiliation: Department of Neuroscience, One Amgen Center Dr., Thousand Oaks, CA 91320-1799, USA.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Hong
authors.initials: H
authors.lastname: Deng
authors.forename: Lana
authors.initials: L
authors.lastname: Klionsky
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Kuang
authors.forename: April
authors.initials: A
authors.lastname: Le
authors.forename: Doo
authors.initials: D
authors.lastname: Lee
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Louis
authors.forename: Ella
authors.initials: E
authors.lastname: Magal
authors.forename: Barton H
authors.initials: BH
authors.lastname: Manning
authors.forename: John
authors.initials: J
authors.lastname: Rubino
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: Nuria
authors.initials: N
authors.lastname: Tamayo
authors.forename: Tingrong
authors.initials: T
authors.lastname: Wang
authors.forename: Judy
authors.initials: J
authors.lastname: Wang
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.forename: Brad
authors.initials: B
authors.lastname: Youngblood
authors.forename: Maosheng
authors.initials: M
authors.lastname: Zhang
authors.forename: Dawn
authors.initials: D
authors.lastname: Zhu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
mesh_terms: 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*
chemical_list: 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