Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P

J Med Chem. 1996 Aug 2;39(16):3174-8. doi: 10.1021/jm960154i.

Abstract

The application of the concept of backbone cyclization to linear substance P (SP) analogs is presented. We describe the synthesis, characterization, and biological activity of a series of backbone-to-amino-terminus cyclic analogs of the C-terminal hexapeptide of SP. These analogs were designed on the basis of NMR data and molecular modeling of the selective NK-1 analog WS-septide (Ac[Arg6,Pro9]SP6-11). A series of peptides with the general formula: cyclo[-CH2)m-NH-CO-(CH2)n-CO-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2 (n = 2, 3, 6 and m = 2, 3, 4) was synthesized by solid phase methodology using Fmoc chemistry for the main chain and Boc chemistry for the building units [Na-(omega-aminoalkyl)Gly] side chains. Cyclization was performed on the resin after removal of the Boc protecting group from the omega-aminoalkyl chain. Cyclic and precyclic analogs were compared. They were purified by HPLC and characterized by mass spectroscopy and NMR. Biological activity and selectivity to the NK-1 neurokinin receptor were found to depend on cyclization and the ring size: The most active and selective analog had a ring of 20 atoms. This analog was found to have enhanced metabolic stability in various tissue preparation compared to WS-septide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Guinea Pigs
  • Molecular Sequence Data
  • Muscle, Smooth / drug effects
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Pyrrolidonecarboxylic Acid / analogs & derivatives
  • Rats
  • Receptors, Neurokinin-1 / agonists*
  • Receptors, Neurokinin-1 / metabolism
  • Structure-Activity Relationship
  • Substance P / chemical synthesis
  • Substance P / chemistry
  • Substance P / pharmacology*

Substances

  • Peptide Fragments
  • Peptides, Cyclic
  • Receptors, Neurokinin-1
  • Substance P
  • substance P (6-11)
  • Pyrrolidonecarboxylic Acid