Nonpeptide Small Molecule Agonist and Antagonist Original Leads for Neuropeptide FF1 and FF2 Receptors
Nonpeptide Small Molecule Agonist and Antagonist Original Leads for Neuropeptide FF1 and FF2 Receptors
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DOI：
10.1021/jm500989n
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发表时间：
2014-11-13
影响因子：
7.3
通讯作者：
McCurdy, Christopher R.
中科院分区：
文献类型：
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作者：
Journigan, V. Blair;Mesangeau, Christophe;McCurdy, Christopher R.
神经肽FF 1和FF 2受体（NPFF 1-R和NPFF 2-R）及其内源性配体NPFF是负责介导阿片类药物诱导的痛觉过敏、耐受性和依赖性的仅有的几个系统之一。目前，还没有报道对任一亚型显示出良好亲和力或选择性的小分子，以解释NPFF 2-R与阿片类药物介导的镇痛相关的作用，以进一步探索NPFF 1-R，或用于任一亚型的药物开发。我们报告了第一个NPFF 1，2-R，胍基哌啶和SAR研究的非肽小分子支架，发现了NPFF 1激动剂（7 b，Ki = 487 +/- 117 nM），NPFF 1拮抗剂（46，Ki = 81 +/-17 nM）和NPFF 2部分拮抗剂（53 a，Ki = 30 +/-5 nM），其用作开发药理学探针和潜在治疗剂的先导。在小鼠48 ℃温水尾部撤回试验中，单独测试46没有效果，但用46预处理防止NPFF诱导的痛觉过敏。
Neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R), and their endogenous ligand NPFF, are one of only several systems responsible for mediating opioid-induced hyperalgesia, tolerance, and dependence. Currently, no small molecules displaying good affinity or selectivity for either subtype have been reported, to decipher the role of NPFF2-R as it relates to opioid-mediated analgesia, for further exploration of NPFF1-R, or for medication development for either subtype. We report the first nonpeptide small molecule scaffold for NPFF1,2-R, the guanidino-piperidines, and SAR studies resulting in the discovery of a NPFF1 agonist (7b, K-i = 487 +/- 117 nM), a NPFF1 antagonist (46, K-i = 81 +/- 17 nM), and a NPFF2 partial antagonist (53a, K-i = 30 +/- 5 nM), which serve as leads for the development of pharmacological probes and potential therapeutic agents. Testing of 46 alone was without effect in the mouse 48 degrees C warm-water tail-withdrawal test, but pretreatment with 46 prevented NPFF-induced hyperalgesia.