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 KanTM 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.