Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 at the mouse melanocortin receptors Part 3: Modifications at the Arg position

Jerry Ryan Holder, Zhimin Xiang, Rayna M. Bauzo, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The melanocortin pathway is involved in the regulation of several physiological functions including skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. This melanocortin pathway consists of five known G-protein coupled receptors, endogenous agonists derived from the proopiomelanocortin (POMC) gene transcript, the endogenous antagonists Agouti and the Agouti-related protein (AGRP) and signals through the intracellular cAMP signal transduction pathway. The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) located in the brain are implicated as participating in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as α-melanocyte stimulation hormone (α-MSH). All the endogenous (POMC-derived) melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp." Herein, we report 12 tetrapeptides, based upon the template Ac-His6-DPhe7-Arg8-Trp9-NH 2 (α-MSH numbering) that have been modified at the Arg8 position by neutral, basic, or acidic amino acid side chains. These peptides have been pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. The most notable results of this study include the observation that removal of the guanidinyl side chain moiety results in decreased melanocortin receptor potency, but that this Arg8 side chain is not critical for melanocortin receptor agonist activity. Additionally, incorporation of the homoArg8 residue results in 56-fold MC4R versus MC3R selectivity, and the Orn8 residue results in 123-fold MC4R versus MC5R and 63-fold MC5R versus MC3R selectivity.

Original languageEnglish (US)
Pages (from-to)73-82
Number of pages10
JournalPeptides
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2003

Keywords

  • G-protein coupled receptors
  • MTII
  • Melanocortin
  • Melanotropin
  • POMC
  • SHU9119
  • Solid-phase peptide synthesis
  • α-MSH

Fingerprint Dive into the research topics of 'Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH<sub>2</sub> at the mouse melanocortin receptors Part 3: Modifications at the Arg position'. Together they form a unique fingerprint.

Cite this