Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues

J Med Chem. 2003 Nov 6;46(23):4965-73. doi: 10.1021/jm030119t.


It has been shown by extensive studies that melanotropin bioactivities are critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, and in alpha-MSH it has been demonstrated further that a reverse-turn type conformation exists at this pharmacophore. To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in gamma-MSH, two different series of gamma-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R. The 1st series consists of a cyclic scan using different disulfides or lactam bridges. It was found that cyclization of the native gamma-MSH around the highly conserved sequence can lead to shifts in affinity and selectivity for hMC4R instead of the hMC3R as seen in the native peptide. Furthermore, a 23-membered ring is desirable for potency (e.g., analogues 6 and 10) whereas a 26-membered ring (analogue 1, H-Tyr-Val-c[Cys-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH(2) with Gly(4)) is more important for selectivity. The 2nd series is made of d-2-naphthylalanine (d-Nal(2')) scan of the gamma-MSH sequence at position 6 and 8 and the replacement of His(5) with Pro (analogue 13). Analogue 12, H-Tyr-Val-Nle-Gly-His-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a potent and selective antagonist at the hMC4R, and analogue 15, H-Tyr-Val-Nle-Gly-Aib-Phe-Arg-d-Nal(2')-Asp-Arg-Phe-Gly-NH(2), is a highly selective and potent agonist of the hMC5R. A most promising analogue is 13, H-Tyr-Val-Nle-Gly-Pro-d-Nal(2')-Arg-Trp-Asp-Arg-Phe-Gly-NH(2), which is a very potent agonist of the hMC4R, and this analogue can be further evaluated for feeding behavior and the regulation of fat stores.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Cyclic AMP / biosynthesis
  • Cyclization
  • Humans
  • Receptor, Melanocortin, Type 3 / agonists
  • Receptor, Melanocortin, Type 3 / antagonists & inhibitors
  • Receptor, Melanocortin, Type 3 / drug effects*
  • Receptor, Melanocortin, Type 4 / agonists
  • Receptor, Melanocortin, Type 4 / antagonists & inhibitors
  • Receptor, Melanocortin, Type 4 / drug effects*
  • Receptors, Corticotropin / agonists
  • Receptors, Corticotropin / antagonists & inhibitors
  • Receptors, Corticotropin / drug effects*
  • Receptors, Melanocortin
  • Structure-Activity Relationship
  • Transfection
  • gamma-MSH / analogs & derivatives
  • gamma-MSH / chemical synthesis*
  • gamma-MSH / chemistry*
  • gamma-MSH / pharmacology


  • Receptor, Melanocortin, Type 3
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • gamma-MSH
  • melanocortin 5 receptor
  • tyrosyl-valyl-norleucyl-glycyl-prolyl-2'-naphthylalanyl-arginyl-tryptophyl-aspartyl-arginyl-phenylalanyl-glycinamide
  • Cyclic AMP