Effect of a selective and potent central nervous system penetrant, neurokinin-3 receptor antagonist (SB-222200), on cisplatin-induced emesis in the ferret.
The anti-emetic activity of selective NK-1 receptor antagonism is well established. However, little is known of the possibility that other NK receptors might also be involved in the emetic reflex. Given the reported location of NK-3 receptors within the rat brainstem vagal motor and sensory nuclei, we investigated the ability of SB-222200, a brain-penetrant NK-3 receptor antagonist, to interfere with emesis evoked in ferrets by the emetogenic cytotoxic agent cisplatin. In contrast to control anti-emetic experiments using the 5-HT3 receptor antagonist ondansetron, SB-222200 was found to have no effects on cisplatin-induced vomiting or on the associated reductions in feeding and drinking behaviors at any dose tested. We suggest that if NK-3 receptors are involved in the mechanisms of cisplatin-induced nausea and vomiting, they play only a minor role, relative to the major anti-emetic activity exhibited by 5-HT3 or NK-1 receptor antagonism.
King
Andrew G
AG
Department of Microbial, Musculoskeletal, Proliferative Disease Center of Excellence in Drug Discovery (AGK), GlaxoSmithKline, Mail Code UP1450, 1250 S. Collegeville Road, Collegeville, PA 19426-0989, USA. andrew.g.king@gsk.com
Sanger
Gareth J
GJ
D000818:Animals; D000932:Antiemetics / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000627:therapeutic use; D057846:Cell-Penetrating Peptides; D002945:Cisplatin; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005289:Ferrets; D008297:Male; D017294:Ondansetron / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy*
D000932:Antiemetics; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C109112:SB 222200; D017294:Ondansetron; C414409:penetratin; D002945:Cisplatin