Design and synthesis of 1-aminocycloalkane-1-carboxylic acid-substituted deltorphin analogues: unique delta and mu opioid activity in modified peptides

J Med Chem. 1996 Feb 2;39(3):773-80. doi: 10.1021/jm950490j.


Deltorphin analogues were substituted by a series of achiral C alpha,alpha-dialkyl cyclic alpha-amino acids (1-aminocycloalkane-1-carboxylic acids, Ac chi c, where chi = a hexane, pentane, or propane cycloalkane ring) in position 2, 3, 4, or 2 and 3 in deltorphin C, and in position 2 in [Ac6c2,-des-Phe3]deltorphin C hexapeptide. Receptor assays indicated that even though Ac6c2 and Ac6c3 exhibited a diminished Ki delta by ca. 20-fold (2.5-3.3 nM) relative to deltorphin C (Ki delta = 0.15 nM), selectivity was marginally elevated (Ki mu/Ki delta = 1250) or enhanced by about 70%, and both peptides fitted stringent iterative calculations for a two-site binding model (eta = 0.625 and 0.766, respectively, P < 0.0001). The disubstituted [Ac6c2,3]- or [Ac6c2,des-Phe3]deltorphin analogues yielded peptides with decreased Ki delta, such that the latter peptide was essentially inactive. The presence of Ac5c or Ac3c in place of Phe3 further diminished Ki delta (15.4 to 19.0 nM), yet delta selectivity only fell about one-half (Ki mu/Ki delta = 440 and 535, respectively), and only the former peptide fitted a two-site binding model (eta = 0.799). The replacement of Asp4 by Ac6c, Ac5c, or Ac3c produced essentially nonselective analogues through the acquisition of high mu affinities (2.5, 0.58 and 0.27 nM, respectively) while maintaining high delta affinities (Ki delta = 0.045-0.054 nM) which were about 3-fold greater than that of deltorphin C. Using pharmacological assays in vitro (mouse vas deferens and guinea pig ileum), position 3-substituted analogues all indicated substantial losses in bioactivity, whereas substitution by 1-aminocycloalkanes at the fourth position retained high delta activity. In fact, the bioactivity of [Ac3c4]deltorphin C indicated a peptide with relatively weak delta selectivity, which was comparable to the observations with the receptor binding data. In summary, the data confirmed that (i) delta selectivity occurs in the absence of D-chirality at position 2, (ii) the aromaticity of Phe3 is replaceable by an achiral residue with a hydrophobic ring-saturated side chain, and (iii) the acquisition of dual high-affinity analogues occurs through the elimination of the anionic function at position 4 and replacement by an amino acid with a hydrophobic side chain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Guinea Pigs
  • Ileum / drug effects
  • In Vitro Techniques
  • Mice
  • Models, Chemical
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Radioligand Assay
  • Receptors, Opioid, delta / drug effects*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / drug effects*
  • Receptors, Opioid, mu / metabolism


  • Oligopeptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • deltorphin