期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 614, 期 1-3, 页码 50-57出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2009.04.054
关键词
Nociceptin/orphanin FQ; NOP receptor; Compound 24; Calcium mobilization; N/OFQ sensitive tissues; Mouse tail withdrawal assay
资金
- University of Ferrara
- Italian Ministry of University
Compound 24, 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide was recently identified as a nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) ligand. in this study, the in vitro and in vivo pharmacological profiles of Compound 24 were investigated. In vitro studies were performed measuring receptor and [S-35]GTP gamma S binding and calcium mobilization in cells expressing the recombinant NOP receptor as well as using N/OFQ sensitive tissues. In vivo studies were conducted using the tail withdrawal assay in mice. Compound 24 produced a concentration-dependent displacement of [H-3]N/OFQ binding to CHOhNOP cell membranes showing high affinity (pK(i) 9.62) and selectivity (1000 fold) over classical opioid receptors. Compound 24 antagonized with high potency the following in vitro effects of N/OFQ. stimulation of [S-35]GTP gamma S binding in CHOhNOP cell membranes (pA(2) 9.98), calcium mobilization in CHOhNOP cells expressing the G alpha(qi5) chimeric protein (pK(B) 8.73), inhibition of electrically evoked twitches in the mouse (pA(2) 8.44) and rat (pK(B) 8.28) vas deferens, and in the guinea pig ileum (pK(B) 9.12). In electrically stimulated tissues, Compound 24 up to 1 mu M did not modify the effects of classical opioid receptor agonists. Finally in vivo, in the mouse tail withdrawal assay, Compound 24 at 10 mg/kg antagonized the pronociceptive and antinociceptive effects of 1 nmol N/OFQ given supraspinally and spinally, respectively. Under the same experimental conditions Compound 24 did not affect the antinociceptive action of 3 nmol endomorphin-1 injected intrathecally. The present study demonstrated that Compound 24 is a pure, competitive, and highly potent non-peptide NOP receptor selective antagonist. (C) 2009 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据