1992 Volume 65 Issue 4 Pages 1052-1056
A series of phenylalanine homologs with elongated phenylalkyl side chains (R = –(CH2)n-C6H5, n = 1–4) have been incorporated into opioid peptide morphiceptin at position 4 in order to elucidate a role of the amino acid residue in the molecular mechanism of receptor activation. The receptor specificity and selectivity of peptides synthesized were examined in the radio-ligand receptor binding assays using tritiated DAGO- and DADLE-enkephalins. [Phe4]Morphiceptin was most potent for the μ receptors and showed the most pronounced μ/δ-receptor selectivity with a specific ratio of 410. Its μ-affinity was about three times stronger than morphiceptin. All analogs showed very similar CD spectra, suggesting that these peptides have a similar backbone conformation. The results strongly suggest that, besides the backbone conformation, the side-chain aromatic rings at positions 1 (Tyr), 3 (Phe), and 4 (Phe) array in a specific stereoorientation and this array is important to activate μ-receptors. Analogs with longer phenylalkyl side chains appeared not to retain such an arrangement due to the steric hindrance caused by the presence of more than two methylene groups.
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