Synthesis and Opioid Activities of [D-Leu^8]Dynorphin(1-8) Analogs Containing a Reduced Peptide Bond, Ψ(CH_2NH)
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[D-Leu^8]Dynorphin(1-8)-NH_2 analogs, in which each peptide bond was systematically replaced with a ψ(CH_2NH) peptide bond, were synthesized by the solid-phase method. The ψ(CH_2NH) bond was introduced by the Boc-amino acid aldehyde/NaCNBH_3 method on a solid support. In the syntheses of the analogs, undesirable double alkylation took place at the sequences of Tyr^1ψ(CH_2NH)Gly^2 and Gly^2ψ(CH_2NH)Gly^3,possible due to the low steric hindrance of the glycine residue. To suppress the double alkylaiton, a minimum amount of aldehydes was employed. In the receptor binding assay, the ψ(CH_2NH) replacement of N-terminal peptide bonds which led to ^1ψ^2- (2) and ^2ψ^3-analogs (3) resulted in a marked reduction in binding affinities for μ-, δ-, and κ-opioid receptors, while that of the other peptide bonds afforded analogs with a high κ-receptor affinity. A ^3ψ^4-analog (4) showed extremely high κ-receptor selectivity (μ/κ K_i ratio=339,δ/κ K_i ratio=24104). In the in vitro bioactivity assay (guinea pig ileum assay), 2 showed a very low IC_<50> ratio (2.0) in the presence and absence of peptidase inhibitors whereas those of other analogs were >27,suggesting that the introduction of the CH_2NH isostere at Tyr^1-Gly^2 greatly enhanced the enzymatic stability of the parent peptide. Furthermore, analogs 2 and 3 showed a very low sensitivity to the inhibitory effect of NaCl plus 5'-guanylylimidodiphosphate of their binding at a κ-receptor site as compared with the other analogs and the parent peptide. These results suggest that the two analogs (2 and 3) have partial κ-antagonist properties.
- 公益社団法人日本薬学会の論文
- 1995-09-15
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