Abstract
Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.
Highlights
Ghrelin, originally discovered in 1999, is a member of the group of growth hormone secretagogues (GHSs), well-known as hunger-stimulating hormone in humans
A minority of circulating ghrelin undergoes octanoylation,[5] only the octanoylated AG is able to activate the growth hormone secretagogue receptor, a G proteincoupled receptor (GPCR) known as GHS-R1a consisting of 366 amino acid residues.[6]
Pubs.acs.org/jmc in a rat model of postoperative ileus, whereas in a rodent defecation assay only ligand 61 was able to significantly increase the weight of fecal pellets. These results suggest that a peripheral site of action is involved in the stimulation of gastrointestinal transit induced by synthetic GHS-R1a agonists, while the increase of the weight of fecal pellets is mediated by a centrally located site.[129]
Summary
Originally discovered in 1999, is a member of the group of growth hormone secretagogues (GHSs), well-known as hunger-stimulating hormone in humans. The broad spectrum of processes involving ghrelin-dependent pathways opens the opportunity to evaluate new potentially therapeutic approaches for the treatment of several disorders.[10,31,38,47−49] agonists, antagonists, and inverse agonists of the GHS-R1a have been developed over the years.[50−53] ghrelin signaling can be inhibited by blocking GOAT activity Even if this way has not been fully explored yet, it seems to be another promising drug target, as exhaustively described in very recent review articles.[54,55]. The pharmacological effects of the most studied ligands will be discussed
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