Small Molecule Ghrelin Receptor Inverse Agonists and Antagonists

Abstract

Ghrelin is an endogenous peptide hormone secreted primarily by the stomach and is involved in a number of physiological processes including growth hormone secretion, food intake, as well as energy and glucose homeostasis. The physiological actions of ghrelin are mediated through the growth hormone secretagogue receptor 1a (ghrelin receptor), a peptidic G-protein-coupled receptor. This target has attracted much interest, as agents that block ghrelin's actions on its receptor are anticipated to be pharmaceutical interventions for a number of diseases. This review provides an overview of ghrelin biology with a focus on metabolic diseases and summarizes recent medicinal chemistry programs aimed at delivering small molecule ghrelin receptor antagonists and inverse agonists to the clinic.

Development of Fluorinated Non-Peptidic Ghrelin Receptor Ligands for Potential Use in Molecular Imaging

“…For that purpose, the inositol phosphate accumulation assay was used [43,44]. The ghrelin receptor was stimulated with different concentrations of the compounds for 2 h in the absence of ghrelin.…”

“…Their applicability for therapeutic purposes has been investigated in various preclinical and clinical studies [5,40,43,54]. Apart from that, the present study was aimed at investigating the synthesis of parent compounds which fulfill the pharmacological and physicochemical requirements for brain-penetrating receptor ligands and which provide the possibility to introduce fluorine at a position that enables a late-stage incorporation of the positron emitter 18 F. In particular, compound ( S )- 9 , its enantiomer, and the newly synthesized compound ( S )- 16 meet these criteria.…”

“…To date, a variety of small molecules acting at the GhrR was discovered (for a review see [43]). Therefore, we aimed to develop fluorine-bearing highly affine and selective, non-peptidic ligands with physicochemical properties to cross the blood-brain barrier as lead molecule(s) to establish in the following step an 18 F-labeled radiotracer for PET qualified for GhrR imaging and quantification.…”

New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists

“…Overall, the binding affinities were in the nanomolar range for the most potent ligands (compounds [13][14][15][16][17][18] with IC 50 values between 0.7 and 6 nM while compound 6, with a free amine, lost its binding affinity (IC 50 >1000 nM). This indicates that substitution of the N-terminal amino function by an acylating group such as the pyridyl ring remains essential for the compounds to bind to the receptor.…”

“…9 Numerous nonpeptide small molecules such as benzodiazepine, 10 piperazine bisamide, 11 azaquinazolinone 12 and indolinone 13 derivatives have been described as potent antagonists of the ghrelin receptor. 14 In our effort to find new ghrelin receptor ligands, we recently described a family of peptidomimetics based on a decorated 1,2,4-triazole scaffold that led to potent agonists and antagonists of this receptor. [15][16][17] These compounds were synthesized from (D)tryptophan residue as starting material and present in their final structure only one asymmetric carbon atom, whose configuration was controlled during the synthetic process.…”