title: 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.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: E J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: E
authors.initials: E
authors.lastname: Ber
authors.forename: J J
authors.initials: JJ
authors.lastname: Hale
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: E
authors.initials: E
authors.lastname: Seward
authors.forename: I
authors.initials: I
authors.lastname: Huscroft
authors.forename: S
authors.initials: S
authors.lastname: Owen
authors.forename: C J
authors.initials: CJ
authors.lastname: Swain
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002945:Cisplatin / Q000037:antagonists & inhibitors; D003001:Cloning, Molecular; D006224:Cricetinae; D005289:Ferrets; D005849:Gerbillinae; D006801:Humans; D007262:Infusions, Intravenous; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000932:Antiemetics; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; C068032:GR 73632; D013373:Substance P; D002945:Cisplatin