Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

Abstract

Ghrelin is a unique bioactive peptide with respect to both the structure and its biological function. This 28-amino acid peptide is modified with an n-octanoyl group at serine-3, and accordingly is the only lipidated biologically active peptide hormone known so far. Ghrelin binds to the so-called ghrelin or GHS receptor, a member of the class A of G-protein coupled receptors, which leads to Ca(2+) release intracellularly due to the activation of the Gq-system. Interestingly, the ghrelin receptor shows a significant constitutive activity which means that in addition to agonists and antagonists, inverse agonists play an important role in receptor modulation. In this review, the major activities of ghrelin are summarized with a strong focus on the regulation of food intake. So far reported agonists, antagonists and inverse agonists are shown and structure activitiy relationships are discussed. Furthermore, the application of ghrelin ligands as novel anti-obesity drugs is outlined and the state of the art in this field is summarized.

Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin- and melanocortin-3 receptors

“…For example, female MC3R knock-out mice demonstrate a reduced response to ghrelin (52), indicating that more components are probably involved in this homeostatic system. Alternative therapeutic strategies focus on the inactivation of leptin-independent pathways such as ghrelin and its receptor (53,54).…”

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

“…Ghrelin is the only known gut-peptide exerting an orexigenic effect via the activation of the centrally expressed GHS-R1a receptor [3][4][5][6] and has thus received much attention as an antiobesity drug target [7][8][9][10][11][12][13][14][15][16] . However, despite previous and ongoing drug development efforts, no weight-loss drugs that target the ghrelin receptor are currently on the market.…”

The Peptidic GHS-R antagonist [D-Lys3]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity

“…agonists have been developed and tested as promising anti-obesity agents (Asakawa et al, 2003;Castañeda et al, 2010;Chollet et al, 2009;Esler et al, 2007;Moulin et al, 2007;Nogueiras et al, 2006 ]substance P) (Cheng et al, 1997).…”