Studies Opioid Antagonist Peptides with Retro-Orientation

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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.