Synthesis and pharmacological activity of the N‐terminal dermorphin tetrapeptide analogs with CH2‐NH peptide bond isosteres

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Abstract
The synthesis of pseudotetrapeptides H‐Tyr‐D‐Ala‐Phe‐NH‐(CH2)2‐NH2 (1a), H‐Tyr‐D‐Ala‐Phe‐ψ(CH2‐NH)‐Gly‐NH2 (2a), H‐Tyr‐D‐Ala‐ψ(CH2‐NH)‐Phe‐Gly‐NH2 (3a), and H‐Tyr‐ψ(CH2‐NH)‐D‐Ala‐Phe‐Gly‐NH2 (4a), representing the N‐terminal tetrapeptide sequence of dermorphin, in which amide bonds are replaced by CH2‐NH bond, is described. N‐acetyl‐Tyr and desamino‐Tyr pseudopeptide analogs (1‐4b), (1‐3c) are also described. The analogs were assayed in binding studies based on displacement of μ and δ‐receptor selective radiolabels from rat brain membrane and in a bioassay using guinea pig ileum (GPI). Pseudopeptides in which the C‐terminal (1a) or D‐Ala‐Phe (3a) amide bond are substituted, exhibit higher μ‐affinities and μ‐receptor selectivity than the corresponding Phe‐Gly or Tyr‐D‐Ala analogs (2a, 4a). Acetyl‐and desamino‐Tyr pseudopeptide analogs (1‐4b) and (1‐3c) did not exhibit μ and δ‐opioid receptor affinity at nM concentration. The relevance of the single peptide replacement and of its association to acetylation or amino group elimination of Tyr, is discussed on the basis of a receptor model for μ and δ opioids.