KARIs, Ghrelin Receptor Agonists With Excellent Brain Permeability, Increase Food Intake and Attenuate the Muscle Loss in Mice.

backgroundGhrelin regulates appetite, gastrointestinal motility and growth hormone (GH) secretion through activation of the growth hormone secretagogue receptor (GHSR-1a) in hypothalamic neurons, with downstream effects on adipose tissue and skeletal muscle. Although ghrelin and synthetic GHSR-1a agonists have been investigated for the treatment of anorexia, sarcopenia and cancer cachexia, their clinical utility has been limited by unfavourable pharmacokinetics. We recently discovered a novel class of small-molecule compounds, termed KARIs, which act as potent GHSR-1a agonists with excellent brain permeability. Here, we evaluated their efficacy as GHSR-1a agonists in vitro and in vivo.

methodGHSR-1a agonistic effects of KARIs were assessed using calcium influx and competitive binding assays in human GHSR-1a-expressing cells, and molecular docking simulations were conducted. Pharmacokinetic properties of KARIs (1 mg/kg i.v, 10 mg/kg p.o) were compared with anamorelin (3 mg/kg i.v., 30 mg/kg p.o.). In vivo efficacy was evaluated in mouse models of postoperative ileus (POI; 10, 20 or 30 mg/kg), age-related sarcopenia (10 mg/kg/day for 4 weeks) and cancer cachexia (10 or 30 mg/kg/day from Days 9 to 24 after CT26 tumour induction).

resultsKARIs directly interacted with key GHSR-1a residues (Phe279) and increased calcium influx (EC

conclusionsKARIs are potent, brain-penetrant GHSR-1a agonists with favourable pharmacokinetics compared to anamorelin. They enhance appetite, preserve skeletal muscle mass and improve physical performance in models of aging and cancer cachexia, supporting their potential as next-generation therapies for anorexia and muscle wasting.