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

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• 作者：Caroline Proulx ; 脡milie Picard ; Damien Boeglin ; Petra Pohankova ; Sylvain Chemtob ; Huy Ong ; William D. Lubell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6502-6511
• 全文大小：395K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

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 (33) all exhibited antiangiogenic activity.