Studies Opioid Antagonist Peptides with Retro-Orientation

我们得到了许多在氨基末端含有tyr1 - och_3的阿片拮抗剂肽。对于这些拮抗剂肽，假设了一个反向定向模型，其中肽以与激动剂肽相反的方向与阿片受体结合。类阿片拮抗剂肽如casoxin 6 （Ser-Arg-Tyr-Pro-Ser-Tyr-OCH_3）、casoxin 5 （Arg-Tyr-Pro-Ser-Tyr-OCH_3）、casoxin 4 （Tyr-Pro-Ser-Tyr-OCH_3）、lactoferroxin B （arg - tyr -Leu- gly - gly - tyr - och_3）、lactoferroxin C （Lys-Tyr-Leu-Gly-Pro-Gln-Tyr-OCH_3）、retro-[Leu] enkephalin methyllester和retro-dynorphin A [1-13] methyllester均符合该模型。这些多肽以通式X_a-Aromatic-X_b-Tyr-X_c表示。当xa为碱性残基时，拮抗剂肽对kappa亚型阿片受体具有亲和力。这与阿片受体激动剂肽以通式x_a - tyr - x_b - aromatic_x_c表达形成鲜明对比，当X_c为基本残基时，肽对kappa亚型阿片受体表现出选择性。在这种反向定向模型中，Tyr残基的氨基没有投射到受体上的适当位置。因此，尽管多肽对阿片受体具有亲和力，但却不具有激动剂活性。其他的阿片拮抗剂肽也不适合逆行定向模型。例如，casoxin A （tir - pro - ser - tir - gly - leu - asn - tyr）、casoxin C （tir - ile - pro - ile - gln - tir - val - leu - ser - arg）均来源于牛kappa-酪蛋白，而casoxin D （tir - val - pro - phe - pro - pro - pro - phe）来源于人alpha_<s1>-酪蛋白，不符合逆向定位模型。阿片拮抗剂的种类似乎很多，因为拮抗剂与受体的结合方式比拮抗剂更多变。

We obtained many opioid antagonist peptides which have Tyr-OCH_3 at their amino termini. For theses antagonist peptides, a retro-orientation model, in which the peptides bind to the opioid receptors just in a reverse orientation to that of the agonist peptides, was postulated. Opioid antagonist peptides such as casoxin 6 (Ser-Arg-Tyr-Pro-Ser-Tyr-OCH_3), casoxin 5 (Arg-Tyr-Pro-Ser-Tyr-OCH_3), casoxin 4 (Tyr-Pro-Ser-Tyr-OCH_3), lactoferroxin A (Tyr-Leu-Gly-Ser-Gly-Tyr-OCH_3), lactoferroxin B (Arg-Tyr-Tyr-Gly-Tyr-OCH_3), lactoferroxin C (Lys-Tyr-Leu-Gly-Pro-Gln-Tyr-OCH_3), retro-[Leu] enkephalin methylester and retro-dynorphin A [1-13] methylester fit to this model. These peptides are expressed in a general formula, X_a-Aromatic-X_b-Tyr-X_c. The antagonist peptides had affinity for kappa-subtype opioid receptor when X_a were basic residues. This is a good contrast to that opioid agonist peptides are expressed in a genaral formula, X_a-Tyr-X_b-Aromatic-X_c, and that the peptides show selectivity for kappa-subtype opioid receptors when X_c are basic residues. In such a retro-orientation model, amino group of Tyr residue is not projected to a proper site on the receptors. For this reason, the peptides could not have the agonist activity in spite of the affinities to the opioid receptors.Other opioid antagonist peptides which do not fit to the retro-orientation model were also obtained. For example, casoxin A (Tyr-Pro-Ser-Tyr-Gly-Leu-Asn-Tyr), casoxin C (Tyr-Ile-Pro-Ile-Gln-Tyr-Val-Leu-Ser-Arg) both derived bovine kappa-casein, and casoxin D (Tyr-Val-Pro-Phe-Pro-Pro-Phe) derived from human alpha_<s1>-casein do not fit to the retro-orientation model. There seems to be many types of opioid antagonists because manner of the binding between the antagonists and receptors are more variable than that of the antagonists.