Neurobiology, Pharmacology, and Medicinal Chemistry of Neuropeptide S and Its Receptor
Neurobiology, Pharmacology, and Medicinal Chemistry of Neuropeptide S and Its Receptor
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DOI：
10.1002/med.20180
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发表时间：
2010-09-01
影响因子：
13.3
通讯作者：
Calo, Girolamo
中科院分区：
文献类型：
--
作者：
Guerrini, Remo;Salvadori, Severo;Calo, Girolamo
神经肽S（Neuropeptide S，NPH）是通过反向药理学技术鉴定的最后一种神经肽。NPSR选择性结合并激活先前的孤儿GPCR，现在称为NPSR，产生细胞内钙动员和cAMP水平增加。由NPSR/NPSR系统调节的生物功能包括焦虑、唤醒、运动、食物摄入、记忆和药物成瘾。NPS的一级序列（在人类中SFRNGVGTGMKKTSFQRAKS）在脊椎动物中高度保守，尤其是在N末端。丙氨酸和D扫描研究表明，分子的这一部分对生物活性至关重要。对Phe（2）、Arg（3）和Asn（4）进行的重点结构-活性研究证实了这一指示，并揭示了这些位置对NPSR结合和激活的化学要求。序列Gly（5）-瓦尔（6）-Gly（7）似乎对于形成肽的生物活性构象是重要的。对Gly（5）的结构活性研究使得能够鉴定第一代肽能NPSR纯拮抗剂，包括[D-Cys（tBu）（5）] NPSr和[D-Val（5）] NPSr，其拮抗剂性质在体内得到证实。最后，最近公布了取代的双环哌嗪分子（例如SHA 68（3-氧代-1，1-二苯基-四氢-恶唑并[3，4-a]吡嗪-7-羧酸4-氟-苄基酰胺））的药理学特征，使得第一代非肽NPSR拮抗剂可用。在未来的研究中使用NPSR拮抗剂将是至关重要的了解哪些生物功能是由NPSR/NPSR系统控制，并确定选择性NPSR配体的治疗潜力。(C)2009 Wiley Periodicals，Inc. Med Res Rev，30，No. 5，751-777，2010
Neuropeptide S (NPS) is the last neuropeptide identified via reverse pharmacology techniques. NPS selectively binds and activates a previous orphan GPCR, now named NPSR, producing intracellular calcium mobilization and increases in cAMP levels. Biological functions modulated by the NPS/NPSR system include anxiety, arousal, locomotion, food intake, memory, and drug addiction. The primary sequence of NPS (in humans SFRNGVGTGMKKTSFQRAKS) is highly conserved among vertebrates especially at the N-terminus. Ala- and D-scan studies demonstrated that this part of the molecule is crucial for biological activity. Focused structure-activity studies performed on Phe(2), Arg(3), and Asn(4) confirmed this indication and revealed the chemical requirements of these positions for NPSR binding and activation. The sequence Gly(5)-Val(6)-Gly(7) seems to be important for shaping the bioactive conformation of the peptide. Structure activity studies on Gly(5) enabled identification of the first generation of peptidergic NPSR pure antagonists including [D-Cys(tBu)(5)]NPS and [D-Val(5)]NPS whose antagonist properties were confirmed in vivo. Finally, the pharmacological features of substituted bicyclic piperazine molecules (e.g. SHA 68 (3-oxo-1, 1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide) were recently published making available the first generation of nonpeptide NPSR antagonists. The use in future studies of NPSR antagonists will be of paramount importance for understanding which biological functions are controlled by the NPS/NPSR system and for defining the therapeutic potential of selective NPSR ligands. (C) 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 5, 751-777, 2010