Identification and characterization of novel small-molecule protease-activated receptor 2 agonists
(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)
- author
- publishing date
- 2008-12-01
- 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
-
- scopus:57349175016
- pmid:18768780
- 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
- 2024-06-26 04:10:05
@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}}, }