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首页> 美国卫生研究院文献>Molecular Pharmacology >Growth Hormone Secretagogues and Growth Hormone Releasing Peptides Act As Orthosteric Super-Agonists but Not Allosteric Regulators for Activation of the G Protein Gαo1 by the Ghrelin Receptor
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Growth Hormone Secretagogues and Growth Hormone Releasing Peptides Act As Orthosteric Super-Agonists but Not Allosteric Regulators for Activation of the G Protein Gαo1 by the Ghrelin Receptor

机译：生长激素促分泌素和生长激素释放肽充当正构超激动剂但不是变构调节剂可通过Ghrelin受体激活G蛋白Gαo1。

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Some growth hormone secretagogues act as agonists at the ghrelin receptor and have been described as “ago-allosteric” ligands because of an ability to also modulate the maximum efficacy and potency of ghrelin (). In membranes prepared from cells coexpressing the human ghrelin receptor and the G protein Gαo1, N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H-indole-3,4′-piperidin)-1′-yl]carbonyl-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide (MK-677), growth hormone-releasing peptide 6 (GHRP-6), and the 2(R)-hydroxypropyl derivative of 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2′-(1H-tetrazol-5-yl) (1,1′-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamide (L-692,585) each functioned as direct agonists, and each displayed higher efficacy than ghrelin. The effect of multiple, fixed concentrations of each of these ligands on the function and concentration-dependence of ghrelin and the effect of multiple, fixed concentrations of ghrelin on the action of MK-677, GHRP-6, and L-692,585 was analyzed globally according to a modified version of an operational model of allosterism that accounts for allosteric modulation of affinity, efficacy, and allosteric agonism. Each of the data sets was best fit by a model of simple competition between a partial and a full agonist. Both positive and negative allosteric modulators are anticipated to alter the kinetics of binding of an orthosteric agonist. However, none of the proposed ago-allosteric regulators tested had any effect on the dissociation kinetics of 125I-[His]-ghrelin, and GHRP-6 and MK-677 were able to fully displace 125I-[His]-ghrelin from the receptor. At least in the system tested, each of the ligands acted in a simple competitive fashion with ghrelin as demonstrated by analysis according to a model whereby ghrelin is a partial agonist with respect to each of the synthetic agonists tested.
机译：一些生长激素促分泌素在ghrelin受体上起激动剂的作用，由于具有调节ghrelin的最大功效和功效的能力，因此被描述为“变构”配体。在由共表达人生长素释放肽受体和G蛋白Gαo1的细胞制成的膜中，N- [1（R）-1，2-二氢-1-乙烷磺酰基螺-3H-吲哚-3,4'-哌啶）-1'-基]羰基-2-（苯基甲氧基）-乙基-2-氨基-2-甲基丙酰胺（MK-677），生长激素释放肽6（GHRP-6）和3-氨基-的2（R）-羟丙基衍生物3-甲基-N-（2,3,4,5-四氢-2-氧-1-（[2'-（1H-四唑-5-基）（1,1'-联苯）-4-基]甲基）-1H-1-苯并ze庚因-3（R）-基）-丁酰胺（L-692,585）均起直接激动剂的作用，且均比生长激素释放肽高。全局分析了每种配体的多个固定浓度对ghrelin的功能和浓度依赖性的影响，以及多个固定浓度的ghrelin对MK-677，GHRP-6和L-692,585的作用的影响根据变构操作模型的修改版，解释了亲和力，功效和变构激动作用的变构调节。每个数据集最适合部分激动剂和完全激动剂之间简单竞争的模型。正和负变构调节剂都有望改变正构激动剂的结合动力学。但是，测试的拟议的变构调节剂均未对 125 I- [His] -ghrelin的解离动力学产生任何影响，GHRP-6和MK-677能够完全取代受体> 125 I- [His] -ghrelin。至少在所测试的系统中，每个配体以与生长素释放肽的简单竞争方式起作用，如通过根据模型的分析所证明的，其中生长素释放肽相对于每个测试的合成激动剂是部分激动剂。

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