Design and synthesis of motilin antagonists derived from the [1-4] fragment of porcine motilin

J Med Chem. 2002 Jan 31;45(3):670-5. doi: 10.1021/jm010332u.

Abstract

A series of cyclic peptides having the general structure H-Phe-c[-N(epsilon)-Lys-X-NH-(CH(2))(n)-CO-] were designed on the basis of structure-activity relationship studies of motilin. All were motilin antagonists. The cyclic peptides, in which X is a 3-tert-butyl-substituted tyrosine residue (H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-beta Ala-] (3), H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Gly-] (6), H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Abu-] (7), and H-Phe-c[-N(epsilon)-Lys-Tyr(3-tBu)-Ahx-] (8)) showed potent motilin receptor antagonistic activity in the rabbit smooth muscle (pA(2) > 7). The 3-tert-butyl Tyr was found to be the moiety responsible for enhanced binding to the motilin receptor, while the size of the ring had little importance.

MeSH terms

  • Animals
  • In Vitro Techniques
  • Motilin / chemistry*
  • Muscle Contraction
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Peptide Fragments / chemistry*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Rabbits
  • Receptors, Gastrointestinal Hormone / antagonists & inhibitors*
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Peptide Fragments
  • Peptides, Cyclic
  • Receptors, Gastrointestinal Hormone
  • Receptors, Neuropeptide
  • motilin receptor
  • Motilin