Advanced

Identification and characterization of novel small-molecule protease-activated receptor 2 agonists

Gardell, Luis R. ; Ma, Jian Nong ; Seitzberg, Jimmi Gerner ; Knapp, Anne E. ; Schiffer, Hans H. ; Tabatabaei, Ali ; Davis, Christopher N. ; Owens, Michelle ; Clemons, Bryan and Wong, Kenneth K. , et al. (2008) In Journal of Pharmacology and Experimental Therapeutics 327(3). p.799-808
Abstract

We report the first small-molecule protease-activated receptor (PAR) 2 agonists, AC-55541 [N-[[1-(3-bromo-phenyl)-eth-(E)-ylidene-hydrazinocarbonyl]- (4-oxo-3,4-dihydro-phthalazin-1-yl)-methyl]-benzamide] and AC-264613 [2-oxo-4-phenylpyrrolidine-3-carboxylic acid [1-(3-bromo-phenyl)-(E/Z)- ethylidene]-hydrazide], each representing a distinct chemical series. AC-55541 and AC-264613 each activated PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca2+ mobilization assays, with potencies ranging from 200 to 1000 nM for AC-55541 and 30 to 100 nM for AC-264613. In comparison, the PAR2-activating peptide 2-furoyl-LIGRLO-NH 2 had similar potency, whereas SLIGRL-NH2 was... (More)

We report the first small-molecule protease-activated receptor (PAR) 2 agonists, AC-55541 [N-[[1-(3-bromo-phenyl)-eth-(E)-ylidene-hydrazinocarbonyl]- (4-oxo-3,4-dihydro-phthalazin-1-yl)-methyl]-benzamide] and AC-264613 [2-oxo-4-phenylpyrrolidine-3-carboxylic acid [1-(3-bromo-phenyl)-(E/Z)- ethylidene]-hydrazide], each representing a distinct chemical series. AC-55541 and AC-264613 each activated PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca2+ mobilization assays, with potencies ranging from 200 to 1000 nM for AC-55541 and 30 to 100 nM for AC-264613. In comparison, the PAR2-activating peptide 2-furoyl-LIGRLO-NH 2 had similar potency, whereas SLIGRL-NH2 was 30 to 300 times less potent. Neither AC-55541 nor AC-264613 had activity at any of the other PAR receptor subtypes, nor did they have any significant affinity for over 30 other molecular targets involved in nociception. Visualization of EYFP-tagged PAR2 receptors showed that each compound stimulated internalization of PAR2 receptors. AC-55541 and AC-264613 were well absorbed when administered intraperitoneally to rats, each reaching micromolar peak plasma concentrations. AC-55541 and AC-264613 were each stable to metabolism by liver microsomes and maintained sustained exposure in rats, with elimination half-lives of 6.1 and 2.5 h, respectively. Intrapaw administration of AC-55541 or AC-264613 elicited robust and persistent thermal hyperalgesia and edema. Coadministration of either a tachykinin 1 (neurokinin 1) receptor antagonist or a transient receptor potential vanilloid (TRPV) 1 antagonist completely blocked these effects. Systemic administration of either AC-55541 or AC-264613 produced a similar degree of hyperalgesia as was observed when the compounds were administered locally. These compounds represent novel small-molecule PAR2 agonists that will be useful in probing the physiological functions of PAR2 receptors.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Pharmacology and Experimental Therapeutics
volume
327
issue
3
pages
10 pages
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • pmid:18768780
  • scopus:57349175016
ISSN
0022-3565
DOI
10.1124/jpet.108.142570
language
English
LU publication?
no
id
84162912-3e5a-4706-a500-e00980199342
date added to LUP
2019-10-02 10:16:08
date last changed
2020-07-16 03:38:19
@article{84162912-3e5a-4706-a500-e00980199342,
  abstract     = {<p>We report the first small-molecule protease-activated receptor (PAR) 2 agonists, AC-55541 [N-[[1-(3-bromo-phenyl)-eth-(E)-ylidene-hydrazinocarbonyl]- (4-oxo-3,4-dihydro-phthalazin-1-yl)-methyl]-benzamide] and AC-264613 [2-oxo-4-phenylpyrrolidine-3-carboxylic acid [1-(3-bromo-phenyl)-(E/Z)- ethylidene]-hydrazide], each representing a distinct chemical series. AC-55541 and AC-264613 each activated PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca<sup>2+</sup> mobilization assays, with potencies ranging from 200 to 1000 nM for AC-55541 and 30 to 100 nM for AC-264613. In comparison, the PAR2-activating peptide 2-furoyl-LIGRLO-NH <sub>2</sub> had similar potency, whereas SLIGRL-NH<sub>2</sub> was 30 to 300 times less potent. Neither AC-55541 nor AC-264613 had activity at any of the other PAR receptor subtypes, nor did they have any significant affinity for over 30 other molecular targets involved in nociception. Visualization of EYFP-tagged PAR2 receptors showed that each compound stimulated internalization of PAR2 receptors. AC-55541 and AC-264613 were well absorbed when administered intraperitoneally to rats, each reaching micromolar peak plasma concentrations. AC-55541 and AC-264613 were each stable to metabolism by liver microsomes and maintained sustained exposure in rats, with elimination half-lives of 6.1 and 2.5 h, respectively. Intrapaw administration of AC-55541 or AC-264613 elicited robust and persistent thermal hyperalgesia and edema. Coadministration of either a tachykinin 1 (neurokinin 1) receptor antagonist or a transient receptor potential vanilloid (TRPV) 1 antagonist completely blocked these effects. Systemic administration of either AC-55541 or AC-264613 produced a similar degree of hyperalgesia as was observed when the compounds were administered locally. These compounds represent novel small-molecule PAR2 agonists that will be useful in probing the physiological functions of PAR2 receptors.</p>},
  author       = {Gardell, Luis R. and Ma, Jian Nong and Seitzberg, Jimmi Gerner and Knapp, Anne E. and Schiffer, Hans H. and Tabatabaei, Ali and Davis, Christopher N. and Owens, Michelle and Clemons, Bryan and Wong, Kenneth K. and Lund, Birgitte and Nash, Norman R. and Gao, Yan and Lameh, Jelveh and Schmelzer, Kara and Olsson, Roger and Burstein, Ethan S.},
  issn         = {0022-3565},
  language     = {eng},
  month        = {12},
  number       = {3},
  pages        = {799--808},
  publisher    = {American Society for Pharmacology and Experimental Therapeutics},
  series       = {Journal of Pharmacology and Experimental Therapeutics},
  title        = {Identification and characterization of novel small-molecule protease-activated receptor 2 agonists},
  url          = {http://dx.doi.org/10.1124/jpet.108.142570},
  doi          = {10.1124/jpet.108.142570},
  volume       = {327},
  year         = {2008},
}