title: Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets.
abstract: These studies have compared the pharmacological profile of two non-peptide human type neurokinin1 (hNK1) receptor selective antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand binding studies L-741,671 and L-743,310 had high affinity for ferret and cloned hNK1 receptors [Ki (nM) ferret 0.7 and 0.1; human 0.03 and 0.06, respectively] but low affinity for rodent NK1 receptors [Ki (nM) 64 and 17, respectively] suggesting that ferret receptors have hNK1-like binding pharmacology. Studies in vivo showed that L-741,671 and L-743,310 had equivalent functional activity in the periphery (ID50s of 1.6 and 2 micrograms/kg i.v., respectively) as measured by inhibition of plasma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion technique in anaesthetised rats, L-741,671 was shown to be much more brain penetrant than the quaternary compound L-743,310 which had an entry rate similar to the poorly brain penetrant plasma marker inulin. These compounds thus provided an opportunity to compare the anti-emetic effects of equi-active hNK1 receptor antagonists with and without brain penetration to central NK1 receptor sites. When tested against cisplatin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) produced marked dose-dependent inhibition of retching and vomiting but L-743,310 was inactive at 3 and 10 micrograms/kg i.v. In contrast, direct central injection of L-741,671 and L-743,310 (30 micrograms) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 micrograms) intracisternally was shown to inhibit retching and vomiting induced by i.v. cisplatin. L-741,671 and L-743,310 had equivalent functional activity, at the same dose, against cisplatin-induced emesis when injected centrally. These observations indicated that had L-743,310 penetrated into the brain after systemic administration it would have been active in the cisplatin-induced emesis assay and so show that brain penetration is essential for the anti-emetic action of systemically administered NK1 receptor antagonists.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, U.K.
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: B
authors.initials: B
authors.lastname: Francis
authors.forename: D
authors.initials: D
authors.lastname: Pearce
authors.forename: K
authors.initials: K
authors.lastname: Merchant
authors.forename: A M
authors.initials: AM
authors.lastname: MacLeod
authors.forename: T
authors.initials: T
authors.lastname: Ladduwahetty
authors.forename: L
authors.initials: L
authors.lastname: Keown
authors.forename: C
authors.initials: C
authors.lastname: Swain
authors.forename: R
authors.initials: R
authors.lastname: Baker
authors.forename: M
authors.initials: M
authors.lastname: Cascieri
authors.forename: E
authors.initials: E
authors.lastname: Ber
authors.forename: J
authors.initials: J
authors.lastname: Metzger
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D001798:Blood Proteins / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004224:Diterpenes / Q000037:antagonists & inhibitors / Q000633:toxicity; D005289:Ferrets / Q000502:physiology*; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000932:Antiemetics; D000970:Antineoplastic Agents; D001798:Blood Proteins; D004224:Diterpenes; D007211:Indoles; C105217:L 741671; C105218:L 743310; D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D009498:Neurotoxins; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D014230:Triazoles; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; C024353:resiniferatoxin; D002945:Cisplatin