Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets.
We have developed a non-peptide compound, HSP-117, antagonist of the tachykinin NK-1 receptor. Binding of 3H-substance P (SP) to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being about 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. These results indicate that (1) HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the nucleus tractus solitarius and (2) NK-1 receptors in the nucleus tractus solitarius play an important role in emesis induced by broad-spectrum emetic stimuli.
Saito
R
R
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan. rsaito@psat.fukuoka-u.ac.jp
Suehiro
Y
Y
Ariumi
H
H
Migita
K
K
Hori
N
N
Hashiguchi
T
T
Sakai
M
M
Saeki
M
M
Takano
Y
Y
Kamiya
H
H
D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D019327:Copper Sulfate; D004639:Emetics; D005289:Ferrets; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D014839:Vomiting / Q000517:prevention & control
D000932:Antiemetics; D001572:Benzofurans; D004639:Emetics; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D009020:Morphine; C119466:HSP 117; D019327:Copper Sulfate