In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists.

Abstract

The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (D-Ala-[L-Pro9,Me-Leu8]substance P-(7-11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (+)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin- 3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2, 4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50 < or = 0.85 mg/kg), and acute retching induced by cisplatin (ID50 < or = 0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-m ethoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antagonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50 > 10 mg/kg). High doses (3-10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl] -4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(pi peridinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-emetic in this dose range. SR140333 ((S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3-10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 receptor were highly correlated (r = 0.93, P = 0.0008). Inhibition of foot tapping in gerbils, but not NK1 receptor binding affinity, predicted anti-emetic activity in ferrets (r = 0.75, P < 0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 receptor antagonists is dependent on brain penetration.

• Authors: N M Rupniak, F D Tattersall, A R Williams, W Rycroft, E J Carlson, M A Cascieri, S Sadowski, E Ber, J J Hale, S G Mills, M MacCoss, E Seward, I Huscroft, S Owen, C J Swain, R G Hill, R J Hargreaves
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 326 Issue 2-3 Pg. 201-9 (May 20 1997) ISSN: 0014-2999 [Print] Netherlands
• PMID: 9196273 (Publication Type: Journal Article)

Chemical References

• Antiemetics
• Neurokinin-1 Receptor Antagonists
• Peptide Fragments
• GR 73632
• Substance P
• Cisplatin

Topics

• Administration, Oral
• Animals
• Antiemetics (pharmacology)
• Brain (drug effects, metabolism)
• CHO Cells
• Cisplatin (antagonists & inhibitors)
• Cloning, Molecular
• Cricetinae
• Ferrets
• Gerbillinae
• Humans
• Infusions, Intravenous
• Membranes (drug effects, metabolism)
• Neurokinin-1 Receptor Antagonists
• Peptide Fragments (antagonists & inhibitors)
• Radioligand Assay
• Substance P (analogs & derivatives, antagonists & inhibitors, metabolism)