Superagonism at the human somatostatin receptor subtype 4
Superagonism at the human somatostatin receptor subtype 4
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DOI：
10.1124/jpet.104.075531
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Wurster, S
中科院分区：
文献类型：
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作者：
Engström, M;Tomperi, J;Wurster, S
我们发现了一种新的化合物J-2156 [(1', 2S)-4-氨基- N-（1'-氨基甲酰基-2'-苯乙基）-2-（4 '-甲基-1 '-萘磺酰氨基）丁酰胺]，它属于一类新的生长抑素受体配体。J-2156以纳米摩尔亲和力结合人生长抑素受体亚型4，对其他生长抑素受体具有400倍以上的亚型选择性。在[S-35]鸟苷-5′- o -（3-硫）三磷酸结合试验中，J-2156引起的反应是生长抑素-28和生长抑素-14的2至3倍。生长抑素-14显然不是一种最有效的激动剂，这可以通过证明它在对J-2156进行测试时表现出部分激动剂的典型行为来验证。生长抑素-14浓度的增加导致J-2156的剂量-反应曲线随浓度向右移动，而不影响其最大反应。最大反应没有减少，而且J-2156在膜中检测到优越的疗效，这一事实反对脱敏和内化作为J-2156优越疗效的可能解释。更有可能的是，生长抑素-14和J-2156稳定了不同的受体构象，这些构象与g蛋白相互作用的能力不同。在环AMP实验中，J-2156、生长抑素-28和生长抑素-14都是完全激动剂。然而，这一结果很可能是由于在环AMP实验中存在受体储备，因为环AMP实验中有很大的表观效价增益，并且J-2156比生长抑素的增益更大。我们得出结论，内源性配体生长抑素-14和生长抑素-28不能定义对人生长抑素受体亚型4的最大激动作用，J-2156代表一种所谓的超级激动剂。
We have discovered a novel compound, J-2156 [(1'S, 2S)-4-amino- N-(1'-carbamoyl-2'-phenylethyl)-2-(4"-methyl-1"-naphthalenesulfonylamino) butanamide], that belongs to a new class of somatostatin receptor ligands. J-2156 binds with nanomolar affinity to the human somatostatin receptor subtype 4 and is over 400-fold subtype-selective against the other somatostatin receptors. When evaluated in a [S-35] guanosine-5'-O-(3-thio) triphosphate binding assay, J-2156 elicited a response 2 to 3 times as large as that of somatostatin-28 and somatostatin-14. That somatostatin-14 is clearly not a maximally efficacious agonist could be verified by demonstrating that it displays the typical behavior of a partial agonist when tested against J-2156. Increasing concentrations of somatostatin-14 cause a concentration-dependent rightward shift of the dose-response curves for J-2156, without affecting its maximal response. This lack of reduction of the maximal response and the fact that the superior efficacy of J-2156 is detected in membranes argue against desensitization and internalization as possible explanations for the superior efficacy of J-2156. More likely is that somatostatin-14 and J-2156 stabilize distinct receptor conformations that differ in their ability to interact with G-proteins. In a cyclic AMP assay, J-2156, somatostatin-28, and somatostatin-14 all act as full agonists. However, this outcome is most likely due to the presence of a receptor reserve in the cyclic AMP assay since there is a large gain of apparent potency in the cyclic AMP assay and the gain is larger for J-2156 than for somatostatin. We conclude that the endogenous ligands somatostatin-14 and somatostatin-28 do not define maximal agonism on the human somatostatin receptor subtype 4 and that J-2156 represents a so-called superagonist.