Structure-activity analysis of the growth hormone secretagogue GHRP-6 by alpha- and beta-amino gamma-lactam positional scanning.
Incorporation of amino lactams into biologically active peptides restricts conformational mobility and may enhance selectivity and increase potency. alpha- and beta-amino gamma-lactams (Agl and Bgl), in both S and R configurations, were introduced into the growth hormone secretagogue GHRP-6 using a Fmoc-compatible solid-phase protocol relying on N-alkylation with five- and six-membered cyclic sulfamidates, followed by lactam annulation under microwave heating. Using this protocol in conjunction with IRORI Kan techniques furnished eleven new GHRP-6 analogs, and their binding affinity IC50 values on both the growth hormone secretagogue receptor 1a (GHS-R1a) and CD36 receptors are herein reported. The results indicate that selectivity towards one receptor or the other can be modulated by lactam substitution, typically at the Ala3 and the D-Phe5 positions.
Boutard
Nicolas
N
Chemistry Department, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC H3C 3J7, Canada.
Jamieson
Andrew G
AG
Ong
Huy
H
Lubell
William D
WD
D018955:CD36 Antigens / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism* / Q000502:physiology; D019382:Human Growth Hormone; D007769:Lactams / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D054440:Receptors, Ghrelin / Q000378:metabolism; D047090:beta-Lactams / Q000737:chemistry
D018955:CD36 Antigens; D007769:Lactams; D009842:Oligopeptides; D010446:Peptide Fragments; D054440:Receptors, Ghrelin; D047090:beta-Lactams; D019382:Human Growth Hormone; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone