Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats.
Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats.
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第一种具有全身活性的混合抑制剂前药 RB 101 对脑啡肽代谢酶的抑制可在小鼠和大鼠中诱导有效的镇痛反应。
DOI：
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发表时间：
1992
影响因子：
3.5
通讯作者：
B. Roques
中科院分区：
文献类型：
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作者：
F. Noble;J. Soleilhac;E. Soroca;S. Turcaud;M. Fournie;B. Roques
N-((R，S)-2-苄基-3[(S)(2-氨基-4-甲硫基)丁基二硫]-1-氧丙基)-L-苯丙氨酸苄酯(RB101)是第一个具有系统活性的前药，通过生物依赖的二硫键裂解生成，有效的(S)2-氨基-1-硫基-4-甲硫基丁烷(氨基肽酶N)(IC_(50)=11 NM)和N-[(R，S)-2-mercapto-methyl-1-oxo-3-phenylpropyl]-L-phenylalanine(中性内肽酶)(IC_(50)=2 NM)抑制剂(氨基肽酶N)。RB101很容易通过血脑屏障，静脉注射后观察到对脑内肽酶24.11的完全抑制。给小鼠注射。该前药在小鼠静脉注射后可诱导强烈的、剂量依赖的抗伤害反应。或者南加州大学。目前用于镇痛药筛选的有热板法(ED50=9 mg/kg)和小鼠扭体试验(ED50-3.25 mg/kg)。在大鼠甩尾和尾电刺激实验中，RB101也具有活性。相反，在二硫键形式下，上述选择性氨基肽酶N或内肽酶24.11抑制剂在静脉注射后无效。给药及其联合作用比单独使用RB101的效力小3倍。在所有使用的测试中，RB101的止痛作用可被纳洛酮抑制，但除甩尾和对尾电刺激的运动反应外，不能被Delta型选择性拮抗剂纳曲吲哚所抑制。Rb101-纳洛酮(PA2：7.53+/-0.046)和DAMGO(MU-选择配体)-纳洛酮(PA2：7.38+/-0.049)的表观PA2值相似，表明Mu阿片受体优先参与内源性脑啡肽的镇痛作用，其细胞外水平被两种RB101生成的抑制剂提高。
N-([(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl)-L-phenylalanine benzyl ester (RB101) is the first systemically active prodrug generating through a biologically dependent cleavage of the disulfide bond the potent (S)2-amino-1-mercapto-4-methylthio butane (aminopeptidase N) (IC50 = 11 nM) and N-[(R,S)-2-mercapto-methyl-1-oxo-3-phenylpropyl]-L-phenylalanine (neutral endopeptidase) (IC50 = 2 nM) inhibitors (aminopeptidase N). RB101 easily crosses the blood-brain barrier, as shown by the observed complete inhibition of cerebral endopeptidase 24.11 after i.v. injection in mice. The prodrug induces strong, dose-dependent antinociceptive responses in mice after i.v., i.p. or s.c. administration, in the hot plate (ED50 = 9 mg/kg) and phenylbenzoquinone-induced writhing (ED50-3.25 mg/kg) tests in mice, which are currently used in analgesics screening. RB101 is also active in the tail-flick and tail-electric stimulation tests in rats. In contrast, under disulfide forms, the above selective aminopeptidase N or endopeptidase 24.11 inhibitors are inactive after i.v. administration and their association 3 times less potent than RB101 alone. In all the tests used, the pain-alleviating effect of RB101 was suppressed by naloxone, but, except for the tail-flick and the motor response to tail-electric stimulation, not by the delta-selective antagonist naltrindole. The preferential involvement of mu opioid receptors in the analgesic effects of endogenous enkephalins, whose extracellular levels are increased by the two RB101-generated inhibitors, is suggested by the similar apparent pA2 values for RB101-naloxone (pA2: 7.53 +/- 0.046) and DAMGO (mu-selective ligand)-naloxone (pA2: 7.38 +/- 0.049).(ABSTRACT TRUNCATED AT 250 WORDS)