Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a.

The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the d-Trp2, Ala3, or Trp4 position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the d-Trp2 residue proved important for CD36 receptor affinity; however, His1 could be replaced by Ala1 without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr4]-GHRP-6 (15), [Ala1, azaPhe2]-GHRP-6 (16), and [azaLeu3, Ala6]-GHRP-6 ...