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

被引：104

作者：

Rupniak, NMJ ^{[1
]}

Tattersall, FD ^{[1
]}

Williams, AR ^{[1
]}

Rycroft, W ^{[1
]}

Carlson, EJ ^{[1
]}

Cascieri, MA ^{[1
]}

Sadowski, S ^{[1
]}

Ber, E ^{[1
]}

Hale, JJ ^{[1
]}

Mills, SG ^{[1
]}

MacCoss, M ^{[1
]}

Seward, E ^{[1
]}

Huscroft, I ^{[1
]}

Owen, S ^{[1
]}

Swain, CJ ^{[1
]}

Hill, RG ^{[1
]}

Hargreaves, RJ ^{[1
]}

机构：

[1] MERCK RES LABS,RAHWAY,NJ 07065

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 1997年 / 326卷 / 2-3期

关键词：

anti-emetic; brain penetration; tachykinin NK1 receptor;

D O I：

10.1016/S0014-2999(97)85415-5

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (D-Ala-[L-Pro(9),Me-Leu(8)]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-12,4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50 < 0.85 mg/kg), and acute retching induced by cisplatin (ID50 less than or equal to 0.18 mg/kg). RPR100893 ((3nS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antaonist 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 (N-2-[(4R)-4-hydroxy- 1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methyl-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidinyl)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.

引用

页码：201 / 209

页数：9

共 51 条

[1] 5-HT3 RECEPTOR ANTAGONISTS - AN OVERVIEW OF THEIR PRESENT STATUS AND FUTURE POTENTIAL IN CANCER THERAPY-INDUCED EMESIS [J].