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

Azapeptide analogs 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 analogs featuring Ala1 or His1 and a variety 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 analogs exhibited significant differences in ability to modulate production of nitric oxide (NO) in macrophages and choroidal neovascularization.