title: TRPV1 ligands with hyperthermic, hypothermic and no temperature effects in rats.
abstract: Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX.
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Voight
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Puttfarcken
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dart
authors.affiliation: Research & Development; AbbVie Inc. ; Chicago, IL, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
keywords: 5′-I-RTX, 5′-iodo-resiniferatoxi; 5′-iodo-RTX; Compound 1, (R)-1-(2,2-dimethyl-7-(trifluoromethyl)chroman-4-yl)-3-(3,6-dimethylisoquinolin-5-yl)urea; Compound 2, (R)-1-(2,2-dimethyl-7-(trifluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; Compound 3, (R)-1-(2,2-dimethyl-8-(trifluoromethoxy)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; FLIPR, fluorometric imaging plate reader; OA, osteoarthritis; TRPV1; TRPV1 agonists; TRPV1 antagonists; TRPV1, transient receptor potential vanilloid 1; chromanyl ureas; hyperthermia; hypothermia; thermoregulation