A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage.
A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage.
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黑皮质素单价激动剂 Ac-His-DPhe-Arg-Trp-NH2 与二价激动剂 Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2 的直接体内比较：二价优势
DOI：
10.1021/acschemneuro.6b00399
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发表时间：
2017
影响因子：
5
通讯作者：
Haskell-Luevano,Carrie
中科院分区：
文献类型：
--
作者：
Lensing,CodyJ;Adank,DanielleN;Wilber,StaceyL;Freeman,KatieT;Schnell,SathyaM;Speth,RobertC;Zarth,AdamT;Haskell-Luevano,Carrie
已经开发了靶向假定的黑皮质素受体二聚体的二价配体，并在体外进行了表征;然而，其在体内作用的功能研究受到限制。本报告比较了同二价配体CJL-1-87（Ac-His-DPhe-Arg-Trp-PEDG 20-His-DPhe-Arg-Trp-NH 2）与单价配体CJL-1-14（Ac-His-DPhe-Arg-Trp-NH 2）在小鼠侧脑室中央脑室内（ICV）给药后对能量稳态的影响。二价配体CJL-1-87作为减肥探针在禁食-再喂养体内范例中优于CJL-1-14。与CJL-1-14或盐水相比，用CJL-1-87处理显著减少食物摄入（处理后2-8小时摄入减少50%）。此外，CJL-1-87处理降低了呼吸交换率（RER），而不改变能量消耗，表明脂肪作为主要燃料源被燃烧。另外，CJL-1-87治疗在给药后6小时显著降低体脂质量百分比（p< 0.05），而不改变瘦体重百分比。与CJL-1-14或盐水处理后的水平相比，二价配体显著降低了胰岛素、C肽、瘦素、GIP和Gln血浆水平。或者，胃饥饿素血浆水平显著增加。CJL-1-87和CJL-1-14的血清稳定性（T1/2分别为6.0和16.8 h）足以产生生理效应。CJL-1-14与CJL-1-87结合亲和力的差异被推测为二价配体独特作用的可能机制。我们还提供了体外证据，证明MC 3R-MC 4 R异二聚体复合物的形成，据我们所知，这是第一次，这可能是一个未开发的神经元分子靶点。无论确切的机制如何，CJL-1-87与CJL-1-14相比增加体外结合亲和力、增加作用持续时间（尽管血清稳定性降低）、减少体内食物摄入、减少小鼠体脂百分比和差异性影响小鼠激素水平的有利能力证明了从当前黑皮质素激动剂二价设计策略获得的独特特征。
Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro; however, studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2, to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH2, on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an antiobesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2–8 h after treatment). Furthermore, CJL-1-87 treatment decreased the respiratory exchange ratio (RER) without changing the energy expenditure indicating that fats were being burned as the primary fuel source. Additionally, CJL-1-87 treatment significantly lowered body fat mass percentage 6 h after administration (p< 0.05) without changing the lean mass percentage. The bivalent ligand significantly decreased insulin, C-peptide, leptin, GIP, and resistin plasma levels compared to levels after CJL-1-14 or saline treatments. Alternatively, ghrelin plasma levels were significantly increased. Serum stability of CJL-1-87 and CJL-1-14 (T1/2= 6.0 and 16.8 h, respectively) was sufficient to permit physiological effects. The differences in binding affinity of CJL-1-14 compared to CJL-1-87 are speculated as a possible mechanism for the bivalent ligand’s unique effects. We also provide in vitro evidence for the formation of a MC3R-MC4R heterodimer complex, for the first time to our knowledge, that may be an unexploited neuronal molecular target. Regardless of the exact mechanism, the advantageous ability of CJL-1-87 compared to CJL-1-14 to increase in vitro binding affinity, increase the duration of action in spite of decreased serum stability, decrease in vivo food intake, decrease mice’s body fat percent, and differentially affect mouse hormone levels demonstrates the distinct characteristics achieved from the current melanocortin agonist bivalent design strategy.