Discovery Process and Characterization of Novel Carbohydrazide Derivatives as Potent and Selective GHSR1a Antagonists

Azabicyclo[3.1.0]hexane‐1‐carbohydrazides as Potent and Selective GHSR1a Ligands Presenting a Specific in vivo Behavior

“…In agreement with what was observed previously, [10] the stereochemistry is relevant, and again, enantiomer 2 (that is, the isomer with the higher retention time on the chiral HPLC column) is always more potent than enantiomer 1, at least in the case of the N-methyl derivatives www.chemmedchem.org the bulk of the alkyl group did not result in any significant improvement of the potency profile, but interestingly, the first enantiomer of this series is now the more potent [8 f (e1) fpK i = 8 vs. 8 f (e2) fpK i = 6.8; 8 g (e1) fpK i = 8.6 vs. 8 g (e2) fpK i = 8.4; and 8 h (e1) fpK i = 9 vs. 8 h (e2) fpK i = 6.9]. Further increasing the bulk of the alkyl substituent resulted in a significant decrease in potency (8 e fpK i = 7.9, but with a high IA value at 70 %).…”

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

“…Hence in the absence of ghrelin, the effects of the potential ligands on the receptor should be also considered for ( S )- 9 and the newly synthesized compounds. Indeed, a higher activity GhrR was observed by the addition of compounds ( S )- 9 and ( R )- 9 at a concentration of 10 −5 M. Similar agonistic effects were described for GSK1614343, another non-peptidic ligand [57]. …”

G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

“…The ghrelin peptide mimetic agonist wfw-Isn-NH 2 supports receptor internalization, G q/11 signaling, and ERK1/2 phosphorylation but not SRE-mediated transcriptional activity or food intake (27). GSK161443, a small molecule ghrelin antagonist of calcium mobilization and inositol phosphate turnover (58), acts in vivo as an antagonist of GH release, an inducer of food intake, and a promoter of increased body weight (59,60), but the mechanistic and physiological basis for this has not been determined. Other described small molecule non-peptide agonists (34,61) and antagonists (36,62,63) of GHSR1a have been developed to treat GH deficiency, cachexia, and obesity, and, in a few cases, GH release was discriminated from food intake (59,62,63).…”