Opioid receptor-binding requirements for the delta-selective peptide deltorphin-i - phe(3) 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-GlyNH(2)) 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-(2-thienyl)alanine, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, histidine, and 3-(4-thiazolyl)alanine. mu binding was variable, with K(i)s 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 K-i of 4.79 nM. Within the group of heterocyclic analogs, 3-(2-thienyl)alanine proved to be the best modification, displaying a delta receptor K-i of 1.38 nM, while the polar histidine analog suffered the greatest loss in delta binding (K-i = 317). Compounds containing pyridylalanine and thiazolylalanine were intermediate in binding affinity, with delta K(i)s 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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Heyl, D. L., Dandabathula, M., Kurtz, K. R., & Mousigian, C. (1995). Opioid receptor-binding requirements for the delta-selective peptide deltorphin-i - phe(3) replacement with ring-substituted and heterocyclic amino-acids. Journal of Medicinal Chemistry, 38(7), 1242–1246. doi:10.1021/jm00007a020