N-methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity

J Med Chem. 1992 Jul 24;35(15):2806-11. doi: 10.1021/jm00093a013.


A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Gallbladder / drug effects
  • Guinea Pigs
  • Ileum / drug effects
  • In Vitro Techniques
  • Male
  • Methylation
  • Molecular Sequence Data
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Receptors, Cholecystokinin / metabolism*
  • Sincalide / analogs & derivatives*
  • Sincalide / chemical synthesis
  • Sincalide / metabolism
  • Sincalide / pharmacology
  • Stomach / drug effects


  • Peptide Fragments
  • Receptors, Cholecystokinin
  • cholecystokinin (26-33), N-acetyl-norleucine(28,31)-
  • Sincalide