Guerrini R, Calo' G, Rizzi A, Bigoni R, Rizzi D, Regoli D, Salvadori S
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, via Fossato di Mortara 17/19, 44-100, Ferrara, Italy.
Peptides. 2000 Jul;21(7):923-33. doi: 10.1016/s0196-9781(00)00229-1.
Nociceptin and its receptor (OP(4)) share sequence homologies with the opioid peptide ligand dynorphin A and its receptor OP(2). Cationic residues in the C-terminal sequence of both peptides seem to be required for selective receptor occupation, but the number and the distribution of these basic residues are different and quite critical. Both receptors are presumably activated by the peptides N-terminal sequence (Xaa-Gly Gly-Phe, where Xaa = Phe or Tyr); however, although OP(4) requires Phe(4) as a determinant pharmacophore, OP(2) requires Tyr(1) as do the other opioid receptors. An extensive structure-activity analysis of the N-terminal tetrapeptide has led to conclude that the presence of aromatic residues in position one and four, preferably Phe, as well as the distance between Phe(1) and Phe(4) are extremely critical for occupation and activation of OP(4) in contrast with other opioid receptors (e.g. OP(1), OP(3), OP(2)). Modification of distance between the side chains of Phe(1) and Phe(4) (as obtained with Nphe(1) substitution in both NC and NC(1-13)-NH(2)) and/or conformational orientation of Phe(1) (as in Phe(1)psi(CH(2)-NH)-Gly(2)) has brought to discovery of pure antagonist ([Nphe(1)]-NC(1-13)-NH(2)) and a partial agonist ([Phe(1) psi(CH(2)-NH)-Gly(2)]-NC(1-13)-NH(2)), which have allowed us to characterize and classify the OP(4) receptor in several species. Thus, although antagonist activities at the OP(4) receptor are obtained by chemical modification of Phe(1)-Gly(2) peptide bond or by a shift of Phe(1) side chain of NC peptides, antagonism at the OP(2) receptor requires the diallylation of the N-terminal amino function, for instance, of dynorphin A. These considerations support the interpretation that the two systems nociceptin/OP(4) and dynorphin A/OP(2) are distinct pharmacological entities that differs in both their active sites (Tyr(1) for Dyn A and Phe(4) for NC) and the number and position of cationic residues in the C-terminal portions of the molecules. The chemical features of novel OP(4) receptor ligands either pseudopeptides obtained by combinatorial library screening or molecules of nonpeptide structure are reported and discussed in comparison with NC and NC related peptides.
孤啡肽及其受体（OP(4)）与阿片肽配体强啡肽A及其受体OP(2)具有序列同源性。两种肽的C末端序列中的阳离子残基似乎是选择性占据受体所必需的，但这些碱性残基的数量和分布不同且相当关键。两种受体可能都由肽的N末端序列（Xaa - Gly - Gly - Phe，其中Xaa = Phe或Tyr）激活；然而，尽管OP(4)需要Phe(4)作为决定性药效基团，但OP(2)像其他阿片受体一样需要Tyr(1)。对N末端四肽进行广泛的构效分析得出结论，与其他阿片受体（如OP(1)、OP(3)、OP(2)）相比，第1位和第4位存在芳香族残基，最好是Phe，以及Phe(1)和Phe(4)之间的距离对于OP(4)的占据和激活极其关键。改变Phe(1)和Phe(4)侧链之间的距离（如在NC和NC(1 - 13)-NH(2)中用Nphe(1)取代所获得的）和/或Phe(1)的构象取向（如在Phe(1)psi(CH(2)-NH)-Gly(2)中）已导致发现纯拮抗剂（[Nphe(1)]-NC(1 - 13)-NH(2)）和部分激动剂（[Phe(1) psi(CH(2)-NH)-Gly(2)]-NC(1 - 13)-NH(2)），这使我们能够在几个物种中对OP(4)受体进行表征和分类。因此，尽管通过对Phe(1)-Gly(2)肽键进行化学修饰或通过NC肽的Phe(1)侧链移位可获得OP(4)受体的拮抗活性，但OP(2)受体的拮抗作用需要对N末端氨基功能进行二烯丙基化，例如强啡肽A的N末端氨基功能。这些考虑支持这样的解释，即孤啡肽/OP(4)和强啡肽A/OP(2)这两个系统是不同的药理学实体，它们在活性位点（强啡肽A的Tyr(1)和孤啡肽的Phe(4)）以及分子C末端部分中阳离子残基的数量和位置方面都有所不同。与NC及NC相关肽相比，报告并讨论了新型OP(4)受体配体的化学特征，这些配体要么是通过组合文库筛选获得的假肽，要么是非肽结构的分子。
