Chignen Possi Kelvine, Mulumba Mukandila, Omri Samy, Garcia-Ramos Yesica, Tahiri Houda, Chemtob Sylvain, Ong Huy, Lubell William D
Département de Chimie, ‡Département de Pédiatrie, and §Faculté de Pharmacie, Université de Montréal , C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada.
J Med Chem. 2017 Nov 22;60(22):9263-9274. doi: 10.1021/acs.jmedchem.7b01209. Epub 2017 Nov 1.
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, [A, azaF]- and [azaY]-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 Ala or His 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.
生长激素释放肽-6（GHRP-6）的氮杂肽类似物对分化簇36受体（CD36）表现出有前景的亲和力、选择性和调节剂活性。例如，[A，氮杂F]-和[氮杂Y]-GHRP-6（1a和2b）先前已显示出选择性结合CD36，并在使用脉络膜外植体的微血管发芽试验中分别表现出显著的抗血管生成和轻微的血管生成活性。现在，通过合成和分析一组25种类似物，详细研究了1位和4位残基对这些氮杂肽的亲和力、抗炎和抗血管生成活性的影响，这些类似物在4位氮杂氨基酸残基处具有Ala或His以及各种芳香族侧链。尽管它们的结合亲和力仅相差17倍，但这些类似物在调节巨噬细胞中一氧化氮（NO）的产生和脉络膜新生血管形成的能力上表现出显著差异。
