[3H] - 速激肽与豚鼠回肠纵肌 - 肠肌间神经丛及大脑皮层膜中NK3速激肽受体结合的药理学分析
Pharmacological analysis of [3H]-senktide binding to NK3 tachykinin receptors in guinea-pig ileum longitudinal muscle-myenteric plexus and cerebral cortex membranes.
作者信息
Guard S, Watson S P, Maggio J E, Too H P, Watling K J
机构信息
University Department of Pharmacology, Oxford.
出版信息
Br J Pharmacol. 1990 Apr;99(4):767-73. doi: 10.1111/j.1476-5381.1990.tb13004.x.
Abstract
- The binding properties and pharmacological specificity of the selective NK3 tachykinin receptor agonist [3H))-senktide [( 3H]-succinyl[Asp6,MePhe8] substance P (6-11] have been examined in homogenates of guinea-pig ileum longitudinal muscle-myenteric plexus (LM/MP) and cerebral cortex. 2. Scatchard analysis of saturation binding studies in guinea-pig ileum LM/MP and cerebral cortex membranes indicated that [3H]-senktide bound to a single site with apparent high affinity, KD = 2.21 +/- 0.65 nM; Bmax = 13.49 +/- 0.04 fmol mg-1 protein in ileum and KD = 8.52 +/- 0.45 nM; Bmax = 76.3 +/- 1.6 fmol mg-1 protein in cortex (values are means +/- ranges; n = 2). 3. The pharmacological profile for tachykinins and analogues in displacing [3H]-senktide from ileum membranes was: [MePhe7] neurokinin B greater than neurokinin B (NKB) congruent to senktide greater than eledoisin greater than substance P (SP) greater than neurokinin A(NKA) greater than physalaemin greater than [Sar9,Met(O2)11]SP greater than [Nle10]NKA(4-10) = [Glp6,L-Pro9]-SP(6-11) greater than substance P methyl ester, consistent with [3H]-senktide binding to an NK3 subtype of tachykinin receptor. A similar rank order of affinity was obtained for these peptides in displacing [3H]-senktide from cortex membranes. 4. Several tachykinin receptor agonists were tested for their ability to displace [3H]-senktide from ileal and cortical NK3 binding sites and were found to be either weak displacers (pIC50 less than 5.00) or inactive. 5. The binding of [3H]-senktide to cortex membranes was inhibited by GTP (p1C,0 = 6.49)and GTP-gamma- S (p1C,0 = 6.67) with ATP being at least three orders of magnitude less potent (pIC50 = 3.55). 6. These results indicate that both central and peripheral NK3 receptors share a similar pharmacological specificity and that they may be labelled selectively with the NK3 receptor agonist [3H]-senktide.
摘要
- 已在豚鼠回肠纵肌-肌间神经丛（LM/MP）和大脑皮层匀浆中检测了选择性NK3速激肽受体激动剂[3H]-senktide（[3H]-琥珀酰[天冬氨酸6，甲基苯丙氨酸8]P物质（6-11））的结合特性和药理学特异性。2. 对豚鼠回肠LM/MP和大脑皮层膜中饱和结合研究的Scatchard分析表明，[3H]-senktide以明显的高亲和力结合到单一位点，回肠中KD = 2.21±0.65 nM；Bmax = 13.49±0.04 fmol mg-1蛋白质，皮层中KD = 8.52±0.45 nM；Bmax = 76.3±1.6 fmol mg-1蛋白质（数值为平均值±范围；n = 2）。3. 速激肽及其类似物从回肠膜中置换[3H]-senktide的药理学谱为：[甲基苯丙氨酸7]神经激肽B＞神经激肽B（NKB）≡senktide＞依地多辛＞P物质（SP）＞神经激肽A（NKA）＞physalaemin＞[Sar9，Met（O2）11]SP＞[Nle10]NKA（4-10） = [Glp6，L-脯氨酸9]-SP（6-11）＞P物质甲酯，这与[3H]-senktide结合到速激肽受体的NK3亚型一致。在从皮层膜中置换[3H]-senktide时，这些肽也获得了类似的亲和力排序。4. 测试了几种速激肽受体激动剂从回肠和皮层NK3结合位点置换[3H]-senktide的能力，发现它们要么是弱置换剂（pIC50＜5.00），要么无活性。5. [3H]-senktide与皮层膜的结合受到GTP（pIC50 = 6.49）和GTP-γ-S（pIC50 = 6.67）的抑制，而ATP的效力至少低三个数量级（pIC50 = 3.55）。6. 这些结果表明，中枢和外周NK3受体具有相似的药理学特异性，并且它们可以被NK3受体激动剂[3H]-senktide选择性标记。
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