Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on κ receptor selectivity and potency

Feng Di T. Lung, J. P. Meyer, Bih Show Lou, Li Xiang, Guigen Li, Peg Davis, Irene A. De Leon, Henry I. Yamamura, Frank Porreca, Victor J. Hruby

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Abstract

Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at κ receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [D-Ala3]Dyn A(1-11)-NH2 (2) and [Ala3]Dyn A(1-11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central κ opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1-11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for κ vs μ and κ vs δ receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1-11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for κ opioid receptors. To further investigate structure-activity relationships involving the residue at the 3 position of Dyn A(1-11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for κ, μ, and δ opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1-11)-NH2 generally displayed higher affinity but similar selectivities for the κ receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1-11)-NH2 may play an important role in potency and selectivity for the κ receptor.

Original languageEnglish
Pages (from-to)2456-2460
Number of pages5
JournalJournal of Medicinal Chemistry
Volume39
Issue number13
DOIs
StatePublished - Jun 21 1996

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    Lung, F. D. T., Meyer, J. P., Lou, B. S., Xiang, L., Li, G., Davis, P., De Leon, I. A., Yamamura, H. I., Porreca, F., & Hruby, V. J. (1996). Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on κ receptor selectivity and potency. Journal of Medicinal Chemistry, 39(13), 2456-2460. https://doi.org/10.1021/jm950655o