速激肽NK1受体拮抗剂抗呕吐活性的体外和体内预测指标。
In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists.
作者信息
Rupniak N M, Tattersall F D, Williams A R, Rycroft W, Carlson E J, Cascieri M A, Sadowski S, Ber E, Hale J J, Mills S G, MacCoss M, Seward E, Huscroft I, Owen S, Swain C J, Hill R G, Hargreaves R J
机构信息
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.
出版信息
Eur J Pharmacol. 1997 May 20;326(2-3):201-9. doi: 10.1016/s0014-2999(97)85415-5.
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.
速激肽NK1受体拮抗剂抑制沙鼠中GR73632（D-丙氨酸-[L-脯氨酸9，甲基亮氨酸8]P物质-（7-11））诱导的足部轻拍的能力被用作脑渗透性的间接测量指标，并将其与它们预防雪貂中顺铂诱导的急性呕吐的能力进行比较。（+）-GR203040（（2S，3S和2R，3R）-2-甲氧基-5-四唑-1-基-苄基-（2-苯基-哌啶-3-基）-胺）、CP-99,994（（2S，3S）-顺式-3-（2-甲氧基苄基氨基）-2-苯基哌啶二盐酸盐）和L-742,694（2-（S）-（3,5-双（三氟甲基）苄氧基）-3-（S）-苯基-4-（5-（3-氧代-1,2,4-三唑）甲基吗啉）能有效抑制GR73632诱导的足部轻拍（半数抑制剂量（ID50）≤0.85mg/kg）和顺铂诱导的急性干呕（ID50≤0.18mg/kg）。RPR100893（（3aS，4S，7aS）-7,7-二苯基-4-（2-甲氧基苯基）-2-[(S)-2-（2-甲氧基苯基）丙酰基]全氢异吲哚-4-醇）不是干呕（ID50为4.1mg/kg）或足部轻拍（ID50>10mg/kg）的有效拮抗剂。高剂量（3-10mg/kg）的CGP49823（（2R，4S）-2-苄基-1-（3,5-二甲基苯甲酰基）-N-[(4-喹啉基）甲基]-4-哌啶胺二盐酸盐）、FK888（N2-[(4R)-4-羟基-1-（1-甲基-1H-吲哚-3-基）羰基-L-丙基]-N-甲基-N-苯基甲基-L-3-（2-萘基）-丙酰胺）和LY303870（（R）-1-[N-（2-甲氧基苄基）乙酰氨基]-3-（1H-吲哚-3-基）-2-[N-（2-（4-（哌啶基）哌啶-1-基）乙酰基）氨基]丙烷）需要用于抑制足部轻拍；这些药物在该剂量范围内没有止吐作用。SR140333（（S）-1-[2-[3-（3,4-二氯苯基）-1-（3-异丙氧基苯基乙酰基）哌啶-3-基]乙基]-4-苯基-1-氮杂双环[2.2.2]辛烷；3-10mg/kg）未能抑制足部轻拍或呕吐。对人和雪貂速激肽NK1受体的亲和力高度相关（r = 0.93，P = 0.0008）。沙鼠中足部轻拍的抑制作用而非NK1受体结合亲和力可预测雪貂中的止吐活性（r = 0.75，P < 0.01）。这些发现证实速激肽NK1受体拮抗剂的止吐活性取决于脑渗透性。
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