TACHYKININ NK1 RECEPTOR ANTAGONISTS ACT CENTRALLY TO INHIBIT EMESIS INDUCED BY THE CHEMOTHERAPEUTIC AGENT CISPLATIN IN FERRETS

Citation
Fd. Tattersall et al., TACHYKININ NK1 RECEPTOR ANTAGONISTS ACT CENTRALLY TO INHIBIT EMESIS INDUCED BY THE CHEMOTHERAPEUTIC AGENT CISPLATIN IN FERRETS, Neuropharmacology, 35(8), 1996, pp. 1121-1129
Citations number
27
Categorie Soggetti
Pharmacology & Pharmacy",Neurosciences
Journal title
ISSN journal
00283908
Volume
35
Issue
8
Year of publication
1996
Pages
1121 - 1129
Database
ISI
SICI code
0028-3908(1996)35:8<1121:TNRAAC>2.0.ZU;2-T
Abstract
These studies have compared the pharmacological profile of two non-pep tide human type neurokinin(1) (hNK(1)) receptor selective antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand bindin g studies L-741,671 and L-743,310 had high affinity for ferret and clo ned hNK(1) receptors [K-i (nM) ferret 0.7 and 0.1; human 0.03 and 0.06 , respectively] but low affinity for rodent NK1 receptors [K-i (nM) 64 and 17, respectively] suggesting that ferret receptors have hNK(1)-li ke binding pharmacology. Studies in vivo showed that L-741,671 and L-7 43,310 had equivalent functional activity in the periphery (ID(50)s Of 1.6 and 2 mu g/kg i.v., respectively) as measured by inhibition of pl asma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion tec hnique in anaesthetised rats, L-741,671 was shown to be much more brai n 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 eff ects of equi-active hNK(1) receptor antagonists with and without brain penetration to central NK1 receptor sites. When tested against cispla tin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) pro duced marked dose-dependent inhibition of retching and vomiting but L- 743,310 was inactive at 3 and 10 mg/kg i.v. In contrast, direct centra l injection of L-741,671 and L-743,310 (30 mu g) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 mu g) intracisternall y 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 s ame dose, against cisplatin-induced emesis when injected centrally. Th ese observations indicated that had L-743,310 penetrated into the brai n after systemic administration it would have been active in the cispl atin-induced emesis assay and so show that brain penetration is essent ial for the anti-emetic action of systemically administered NK1 recept or antagonists. Copyright (C) 1996 Elsevier Science Ltd.