Abstract
| Language | English |
|---|---|
| Pages | 361-371 |
| Number of pages | 11 |
| Journal | British Journal of Pharmacology |
| Volume | 158 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Sep 2009 |
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Keywords
- Proteinase-activated receptor 2 (PAR2
- antagonist
- Ca2+ mobilization
- keratinocytes
- radioligand-binding
- thrombin receptor
- smooth-muscle
- human keratinocytes
- nitric-oxide
- inflammation
- par-2
- secretion
- peptide
- cells
- mouse
Cite this
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Novel antagonists for proteinase-activated receptor 2 : Inhibition of cellular and vascular responses in vitro and in vivo. / Kanke, T.; Kabeya, M.; Kubo, S.; Kondo, S.; Yasuoka, K.; Tagashira, J.; Ishiwata, H.; Saka, M.; Furuyama, T.; Nishiyama, T.; Doi, T.; Hattori, Y.; Kawabata, A.; Cunningham, M.R.; Plevin, R.J.
In: British Journal of Pharmacology, Vol. 158, No. 1, 09.2009, p. 361-371.Research output: Contribution to journal › Article
TY - JOUR
T1 - Novel antagonists for proteinase-activated receptor 2
T2 - British Journal of Pharmacology
AU - Kanke, T.
AU - Kabeya, M.
AU - Kubo, S.
AU - Kondo, S.
AU - Yasuoka, K.
AU - Tagashira, J.
AU - Ishiwata, H.
AU - Saka, M.
AU - Furuyama, T.
AU - Nishiyama, T.
AU - Doi, T.
AU - Hattori, Y.
AU - Kawabata, A.
AU - Cunningham, M.R.
AU - Plevin, R.J.
PY - 2009/9
Y1 - 2009/9
N2 - Proteinase-activated receptor 2 (PAR(2)) is a G-protein coupled receptor associated with many pathophysiological functions. To date, the development of PAR(2) antagonists has been limited. Here, we identify a number of novel peptide-mimetic PAR(2) antagonists and demonstrate inhibitory effects on PAR(2)-mediated intracellular signalling pathways and vascular responses. The peptide-mimetic compound library based on the structures of PAR(2) agonist peptides were screened for inhibition of PAR(2)-induced calcium mobilisation in human keratinocytes. Representative compounds were further evaluated by radioligand binding and inhibition of NF kappa B transcriptional activity and IL-8 production. The vascular effects of the antagonists were assessed using in vitro and in vivo models. Two compounds, K-12940 and K-14585, significantly reduced SLIGKV-induced Ca2+ mobilisation in primary human keratinocytes. Both K-12940 and K-14585 exhibited competitive inhibition for the binding of a high-affinity radiolabelled PAR(2)-ligand, [H-3]-2-furoyl-LIGRL-NH2, to human PAR(2) with K-i values of 1.94 and 0.627 mu M respectively. NF kappa B reporter activity and IL-8 production were also significantly reduced. Furthermore, relaxation of rat-isolated aorta induced by SLIGRL-NH2 was inhibited competitively by K-14585. K-14585 also significantly lowered plasma extravasation in the dorsal skin of guinea pigs and reduced salivation in mice. K-12940 and K-14585 antagonized PAR(2) competitively, resulting in inhibition of PAR(2)-mediated signalling and physiological responses both in vitro and in vivo. These peptide-mimetic PAR(2) antagonists could be useful in evaluating PAR(2)-mediated biological events and might lead to a new generation of therapeutically useful antagonists.
AB - Proteinase-activated receptor 2 (PAR(2)) is a G-protein coupled receptor associated with many pathophysiological functions. To date, the development of PAR(2) antagonists has been limited. Here, we identify a number of novel peptide-mimetic PAR(2) antagonists and demonstrate inhibitory effects on PAR(2)-mediated intracellular signalling pathways and vascular responses. The peptide-mimetic compound library based on the structures of PAR(2) agonist peptides were screened for inhibition of PAR(2)-induced calcium mobilisation in human keratinocytes. Representative compounds were further evaluated by radioligand binding and inhibition of NF kappa B transcriptional activity and IL-8 production. The vascular effects of the antagonists were assessed using in vitro and in vivo models. Two compounds, K-12940 and K-14585, significantly reduced SLIGKV-induced Ca2+ mobilisation in primary human keratinocytes. Both K-12940 and K-14585 exhibited competitive inhibition for the binding of a high-affinity radiolabelled PAR(2)-ligand, [H-3]-2-furoyl-LIGRL-NH2, to human PAR(2) with K-i values of 1.94 and 0.627 mu M respectively. NF kappa B reporter activity and IL-8 production were also significantly reduced. Furthermore, relaxation of rat-isolated aorta induced by SLIGRL-NH2 was inhibited competitively by K-14585. K-14585 also significantly lowered plasma extravasation in the dorsal skin of guinea pigs and reduced salivation in mice. K-12940 and K-14585 antagonized PAR(2) competitively, resulting in inhibition of PAR(2)-mediated signalling and physiological responses both in vitro and in vivo. These peptide-mimetic PAR(2) antagonists could be useful in evaluating PAR(2)-mediated biological events and might lead to a new generation of therapeutically useful antagonists.
KW - Proteinase-activated receptor 2 (PAR2
KW - antagonist
KW - Ca2+ mobilization
KW - keratinocytes
KW - radioligand-binding
KW - thrombin receptor
KW - smooth-muscle
KW - human keratinocytes
KW - nitric-oxide
KW - inflammation
KW - par-2
KW - secretion
KW - peptide
KW - cells
KW - mouse
U2 - 10.1111/j.1476-5381.2009.00342.x
DO - 10.1111/j.1476-5381.2009.00342.x
M3 - Article
VL - 158
SP - 361
EP - 371
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 1
ER -