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

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.