Opioid receptor binding requirements for the delta-selective peptide deltorphin. I: Phe3 replacement with ring-substituted and heterocyclic amino acids.
In order to assess steric, lipophilic, and electronic influences on opioid binding affinity, analogs of the delta receptor selective peptide deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2) were prepared in which the residue 3 phenylalanine was replaced with lipophilic fluoro- and methyl-substituted phenylalanines or with the heterocyclic aromatic amino acids 3-(4-thiazolyl)alanine, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, histidine, and 3-(4-thiazolyl)alanine. mu binding was variable, with KiS in excess of 10,000 nM for most analogs, and all of the analogs bound poorly to k receptors. Among the phenyl ring-substituted analogs, those containing the smaller and electron-withdrawing halogens were favored over those with larger, electron-releasing methyl groups, although delta opioid binding affinity was reduced in all cases. The m-fluorophenylalanine analog demonstrated the best delta binding of the group, with a Ki of 4.79 nM. Within the group of heterocyclic analogs, 3-(2-thienyl)alanine proved to be the best modification, displaying a delta receptor Ki of 1.38 nM, while the polar histidine analog suffered the greatest loss in delta binding (Ki = 317). Compounds containing pyridylalanine and thiazolylalanine were intermediate in binding affinity, with delta KiS ranging from 39.5 to 62.4 nM. The major factor influencing the opioid binding of the similar-sized heterocyclic compounds was relative lipophilicity, which outweighed electronic character.
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Department of Chemistry, Eastern Michigan University, Ypsilanti 48197, USA.
Dandabathula
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Kurtz
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Mousigian
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D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D017465:Receptors, Opioid, delta; C059567:deltorphin