Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity
Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity
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DOI：
10.1124/jpet.105.083436
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发表时间：
2005-08-01
影响因子：
3.5
通讯作者：
Petersen, JS
中科院分区：
文献类型：
--
作者：
Kapusta, DR;Thorkildsen, C;Petersen, JS
在清醒的大鼠中，静脉注射六肽Ac-RYYRWK-NH2，一种痛觉肽/孤儿蛋白FQ （N/OFQ）肽（NOP）受体的部分激动剂，产生选择性水利尿，无明显的心血管或行为影响。本研究检测了一种新型且具有潜在代谢稳定性的NOP受体配体ZP120 （ac - ryyrwkkkkkkkkk - nh2）的体外和体内药效学特征，该配体是通过结构诱导探针（SIP）（即K-6序列）偶联到AcRYYRWK-NH2而产生的。在转染人NOP受体的细胞中，Ac-RYYRWK-NH2和ZP120均取代了[H-3] N/OFQ（两种肽，pK(i) = 9.6），并且类似于N/OFQ抑制了forskolin诱导的cAMP形成(Ac-RYYRWK-NH2, pEC(50) = 9.2；ZP120 9.3;N / OFQ, 9.7)。在小鼠输精管实验（MVD）中，Ac-RYYRWK-NH2和ZP120表现为部分激动剂，抑制电诱导的收缩，具有相似的pEC（50）值（分别为9.0和8.6），但与N/OFQ相比，其功效低于最大。在MVD中，两种肽都阻断了对N/OFQ的反应，其中ZP120的效力比Ac-RYYRWK-NH2强约50倍。在体内，大鼠的剂量反应研究表明，在产生钠钾节约的剂量（静脉注射或静脉输注）下，ZP120和Ac-RYYRWK-NH2引起轻度血管扩张反应，无反射性心动过速。然而，肾脏对ZP120的反应更大，持续时间更长。最后，每种肽都能阻断意识大鼠的心动过缓和低血压至N/OFQ，但ZP120的作用持续时间要长得多。总之，这些发现表明，ZP120是一种新型的、功能选择性的sip修饰的NOP受体部分激动剂，具有更高的生物活性和节约钠钾的水生活性，其作用可能有助于管理低钠血症/低钾血症的保水状态。
In conscious rats, intravenous (i.v.)administration of the hexapeptide Ac-RYYRWK-NH2, a partial agonist of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor, produces a selective water diuresis without marked cardiovascular or behavioral effects. The present study examined the in vitro and in vivo pharmacodynamic profile of the novel and potentially metabolically stable NOP receptor ligand ZP120 (Ac-RYYRWKKKKKKK-NH2), which was created by conjugation of a structure-inducing probe ( SIP) (i.e.,K-6 sequence) to AcRYYRWK-NH2. In cells transfected with human NOP receptors, both Ac-RYYRWK-NH2 and ZP120 displaced [H-3] N/OFQ (both peptides, pK(i) = 9.6), and similar to N/OFQ inhibited forskolin-induced cAMP formation (Ac-RYYRWK-NH2, pEC(50) = 9.2; ZP120, 9.3; N/OFQ, 9.7). In the mouse vas deferens assay (MVD), Ac-RYYRWK-NH2 and ZP120 behaved as partial agonists, inhibiting electrically induced contractions with similar pEC(50) values ( 9.0 and 8.6, respectively) but with submaximal efficacy compared with N/OFQ. In MVD, both peptides blocked the responses to N/OFQ, with ZP120 being approximately 50-fold more potent than Ac-RYYRWK-NH2. In vivo, dose-response studies in rats showed that at doses (i.v. bolus or i.v. infusion) that produced a sodium-potassium-sparing aquaresis, ZP120 and Ac-RYYRWK-NH2 elicited a mild vasodilatory response without reflex tachycardia. However, the renal responses to ZP120 were of greater magnitude and duration. Finally, each peptide blocked the bradycardia and hypotension to N/OFQ in conscious rats, but the effect of ZP120 was of much greater duration. Together, these findings demonstrate that ZP120 is a novel, functionally selective SIP-modified NOP receptor partial agonist with increased biological activity and sodium-potassium-sparing aquaretic activity, the actions of which may be useful in the management of hyponatremia/hypokalemia in water-retaining states.