Nonpeptide/peptide chimeric ligands for the nociceptin/orphanin FQ receptor: design, synthesis and in vitro pharmacological activity.
Nonpeptide/peptide chimeric ligands for the nociceptin/orphanin FQ receptor: design, synthesis and in vitro pharmacological activity.
复制标题
伤害感受肽/孤啡肽 FQ 受体的非肽/肽嵌合配体：设计、合成和体外药理活性。
DOI：
10.1111/j.1399-3011.2004.00157.x
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Salvadori,S
中科院分区：
文献类型：
--
作者：
Guerrini,R;Carra',G;Calo',G;Trapella,C;Marzola,E;Rizzi,D;Regoli,D;Salvadori,S
Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the G‐protein coupled receptor referred to as N/OFQ peptide (NOP) receptor. NOP receptor activation by N/OFQ modulates several biological functions both at central and peripheral level. Structure activity relationship (SAR) studies demonstrated that the N/OFQ sequence can be divided into a N‐terminal tetrapeptide ‘message’ crucial for receptor activation and a C‐terminal ‘address’ important for receptor binding. On the basis of this message/address concept we synthesized some chimeric compounds in which we substituted the natural message domain with the nonselective nonpeptide NOP ligand (8‐Naphthalen‐1‐yl‐methyl‐4‐oxo‐1‐phenyl‐1,3,8‐triaza‐spiro[4,5]dec‐3‐yl)‐aceticacid methyl ester (NNC 63‐0532) and used as address domain the peptide sequences Thr‐NH2, N/OFQ(5‐9)‐NH2, N/OFQ(5‐13)‐NH2and N/OFQ(5‐17)‐NH2. All the compounds were pharmacologically evaluated in the electrically stimulated guinea‐pig ileum. NNC 63‐0532 produced a concentration‐dependent inhibition of the electrically induced twitches showing, in comparison with N/OFQ, lower potency and higher maximal effects. In addition, contrary to N/OFQ, the effects of NNC 63‐0532 were insensitive to the NOP selective antagonist [Nphe1, Arg14, Lys15]N/OFQ‐NH2(UFP‐101) while prevented by naloxone. Similar results were obtained with NNC 63‐0532/Thr‐NH2and NNC 63‐0532/N/OFQ(1‐9)‐NH2. On the contrary, the inhibitory effects of NNC 63‐0532/N/OFQ(5‐13)‐NH2and NNC 63‐0532/N/OFQ(5‐17)‐NH2were slightly antagonized by UFP‐101 while naloxone prevented the effects of the high but not of the low concentrations of the two ligands. These data indicate that it is possible to functionalize with the N/OFQ address sequence a nonpeptide NOP ligand for increasing its binding to the NOP receptor. Moreover, these results corroborate the idea that the 5–13 sequence represents the crucial core of the N/OFQ address domain.
