Influences of Histidine-1 and Azaphenylalanine-4 on the Affinity, Anti-inflammatory, and Antiangiogenic Activities of Azapeptide Cluster of Differentiation 36 Receptor Modulators

J Med Chem. 2017 Nov 22;60(22):9263-9274. doi: 10.1021/acs.jmedchem.7b01209. Epub 2017 Nov 1.

Abstract

Azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) exhibit promising affinity, selectivity, and modulator activity on the cluster of differentiation 36 receptor (CD36). For example, [A1, azaF4]- and [azaY4]-GHRP-6 (1a and 2b) were previously shown to bind selectively to CD36 and exhibited respectively significant antiangiogenic and slight angiogenic activities in a microvascular sprouting assay using choroid explants. The influences of the 1- and 4-position residues on the affinity, anti-inflammatory, and antiangiogenic activity of these azapeptides have now been studied in detail by the synthesis and analysis of a set of 25 analogues featuring Ala1 or His1 and a variety of aromatic side chains at the aza-amino acid residue in the 4-position. Although their binding affinities differed only by a factor of 17, the analogues exhibited significant differences in ability to modulate production of nitric oxide (NO) in macrophages and choroidal neovascularization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • CD36 Antigens / chemistry
  • CD36 Antigens / metabolism*
  • Choroid / blood supply
  • Histidine / chemistry*
  • Macrophages / drug effects
  • Mice
  • Neovascularization, Physiologic / drug effects
  • Nitric Oxide / biosynthesis
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemistry
  • Structure-Activity Relationship

Substances

  • Angiogenesis Inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal
  • CD36 Antigens
  • Oligopeptides
  • azaphenylalanine
  • Nitric Oxide
  • Phenylalanine
  • Histidine

Grant support