Ghrelin has well-known activity to stimulate appetite and
weight gain. Evidence suggests that
ghrelin may also have effects in reducing
chemotherapy-induced
emesis via
growth hormone secretagogue receptors (GHS-R1A) in the brain. However, it is not known whether the stimulation of
GHS-R1A has broad inhibitory
anti-emetic effects. In the present studies, we used Suncus murinus to investigate the potential of the new and novel orally bioavailable brain-penetrating
GHS-R1A mimetic,
HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]
urea), to reduce
emesis induced by a variety of
emetic challenges.
HM01 (1 to 30 mg/kg, p.o.) antagonized
emesis induced by
cisplatin (30 mg/kg, i.p.) and by motion (4 cm horizontal displacement, 1 Hz) but was ineffective against
emesis induced by
nicotine (5 mg/kg, s.c.) and
copper sulfate (120 mg/kg by intragastric gavage). In other experiments,
HM01 (3 mg/kg, p.o.) enhanced the
anti-emetic control of a regimen of
palonosetron (0.01 mg/kg, p.o.) alone and
palonosetron (0.01 mg/kg p.o.) plus
netupitant (1 mg/kg, p.o.).
HM01 (10 mg/kg, p.o.) also had positive effects in increasing feeding and drinking in
nicotine-treated animals, and it shortened the latency to drink in animals treated with
cisplatin. These data indicate that brain-penetrating
GHS-R1A agonists may have use alone and/or in combination with standard
anti-emetic regimens for the treatment of
chemotherapy-induced
nausea and
vomiting and
motion sickness.
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