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

Ghrelin 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.

GHSR-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).

KARIs directly interacted with key GHSR-1a residues (Phe279) and increased calcium influx (EC₅₀: KARI 101 = 1.83 ± 1.05 μM; KARI 201 = 3.36 ± 1.09 μM). KARIs showed higher oral bioavailability (BA: KARI 101 = 63%; KARI 201 = 68%) and brain distribution (KARI 101 = 2.2; KARI 201 = 3.7) than anamorelin (BA = 45%, brain distribution = 0.1). KARIs significantly activated hypothalamic neurons (KARI 101 p = 0.029, KARI 201 p = 0.0152), resulting in increased food intake and improved gastric emptying and colonic transit in POI mice. In aged mice, KARIs markedly elevated plasma GH levels and restored gastrocnemius muscle mass (KARI 101 p = 0.0018, KARI 201 p = 0.0006) and improved rota-rod performance (p < 0.0001) by downregulating expression of atrophic genes and upregulating myogenic genes. In cancer cachexia mice, KARIs improved food intake and preserved skeletal muscle mass at lower doses (gastrocnemius, 10 mg/kg; p < 0.0001) than synthetic GHSR - 1a agonist (anamorelin, 30 mg/kg) and enhanced functional recovery (rota-rod test, 10 mg/kg; KARI 101 p = 0.045, KARI 201 p = 0.003) without affecting tumour growth.

KARIs 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.