Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

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.

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“…These heterodimers seemingly activate signaling pathways distinct from those of the constituent monomers and produce different physiological effects. [10][11][12][13][14][15] Resolved X-ray structures for both OX1-R and OX2-R in complex with antagonists and OX2-R in the active state in complex with OX2-R agonists or the endogenous peptide orexin-B have enhanced the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. [16][17][18][19][20][21] Both OX1-R and OX2-R are widely distributed throughout the central nervous system (CNS), located in the ventral tegmental area (VTA), hypothalamus, lateral hypothalamic area, amygdala, and midbrain (Figure 2).…”

“…OX1‐R and OX2‐R can form constitutive homo‐ and heterodimers with each other and with a variety of GPCRs, including cannabinoid CB1 receptor (CB1‐R), opioid κ receptor (KOR), corticotropin‐releasing factor receptor (CRF‐R), cholecystokinin A receptor, serotonin 5‐HT1A receptor (5‐HT1A‐R) and growth hormone secretagogue GHS‐R1a receptor. These heterodimers seemingly activate signaling pathways distinct from those of the constituent monomers and produce different physiological effects 10–15 …”

Establishment of a Cell Line Stably Expressing the Growth Hormone Secretagogue Receptor to Identify Crocin as a Ghrelin Agonist

“…It is known that the half-life of ghrelin in the human body is very short [ 7 ], and thus there is an urgent need for potential ghrelin agonists for the development of new adjuvant therapy. Many ghrelin agonists have been proven to be effective in the management of anorexia, sarcopenia, gastrointestinal diseases, and neurodegenerative disorders [ 8 , 9 ]. However, side effects were reported in patients treated with these agonists, including nausea, musculoskeletal pain, heart failure, hyperglycemia, fluid retention, and inhibition of Cytochrome P450 3A4 [ 10 , 11 ].…”

Computational Investigation of the Impact of the Ghrelin Hormone Gene Variation (R51q) on the Hormone-receptor Binding Pattern

“…13 Endoprotease catalyzes the proteolytic cleavage during the production of ghrelin. 14,15 Yet, it is unclear if this genetic variation alters ghrelin's physiologic characteristics or action.Ghrelin and ghrelin receptor agonists can effectively treat anorexia and cachexia in cancer 16,17 and chronic kidney disease patients. 18 Treatment with ghrelin has been shown to improve renal function and attenuate renal fibrosis and inflammation.…”

“…Ghrelin and ghrelin receptor agonists can effectively treat anorexia and cachexia in cancer 16,17 and chronic kidney disease patients. 18 Treatment with ghrelin has been shown to improve renal function and attenuate renal fibrosis and inflammation.…”