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.

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Indication	Highest Phase	Country/Location	Organization	Date
Vomiting	Discovery	US	Merck & Co., Inc.	-

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