OPIOID RECEPTOR ANTAGONIST AFFINITY LIGANDS - 6-BETA-BROMOACETAMIDO-6-DESOXYNALTREXONE AND 6-BETA-THIOGLYCOLAMIDO-6-DESOXYNALTREXONE
OPIOID RECEPTOR ANTAGONIST AFFINITY LIGANDS - 6-BETA-BROMOACETAMIDO-6-DESOXYNALTREXONE AND 6-BETA-THIOGLYCOLAMIDO-6-DESOXYNALTREXONE
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DOI：
10.1007/bf00968398
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发表时间：
1992-12-01
影响因子：
4.4
通讯作者：
ABOOD, LG
中科院分区：
文献类型：
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作者：
MANDA, S;LERNERMARMAROSH, N;ABOOD, LG
本研究以巯基乙酰氨基为反应基团，合成了一种新的阿片拮抗剂亲和配体6 β-巯基乙酰氨基-6-脱氧纳洛酮（TAN），并与已知的6 β-溴乙酰氨基-6-脱氧纳洛酮（BAN）进行了比较。检测了两种化合物对[H-3]纳洛酮与小牛脑细胞膜结合的可逆和不可逆抑制。BAN和TAN的可逆结合的K（i）值分别为1 x 10（-9）和1 x 10（-10）M，通过log probit图确定。在充分洗涤以除去所有非共价结合的配体后测定不可逆结合。在浓度为5 × 10 ~（-8）和1 × 10 ~（-8）M时，BAN和TAN的不可逆结合被抑制50%的最大值。对[H-3]纳洛酮结合的不可逆抑制的时间过程的研究表明，在1 × 10（-7）M浓度下，最大抑制发生在5 min内。通过扭体试验测定，TAN而非BAN在全身给药时对小鼠产生抗伤害性作用。当脑室内给药时，BAN不阻断吗啡诱导的镇痛作用超过2小时;然而，通过甩尾试验测定，单次ED 50剂量为20纳摩尔的TAN静脉注射吗啡诱导的镇痛作用几乎完全阻断超过24小时。尽管TAN的SH基团是与阿片受体共价相互作用所必需的，但TAN的相互作用位点似乎涉及蛋白质SH基团以外的其他基团。
The present study, utilizing thioglycolamido as the reactive group, describes the synthesis and pharmacology of a new opioid antagonist affinity ligand, 6beta-thioglycolamido-6-desoxynaltrexone (TAN) and compares TAN with a related known compound, 6beta-bromoacetamido-6-desoxynaltrexone (BAN). Both compounds were tested for their reversible and irreversible inhibition of [H-3]naloxone binding to calf brain membranes. Reversible binding of BAN and TAN had K(i) values of 1 x 10(-9) and 1 x 10(-10) M, respectively as determined by log probit plots. Irreversible binding was determined after extensive washing to remove all non-covalently bound ligand. At a concentration of 5 x 10(-8) and 1 x 10(-8) M for BAN and TAN irreversible binding was inhibited 50% of the maximun value. A study of the time course of irreversible inhibition of [H-3]naloxone binding revealed that maximal inhibition occurred within 5 min with a concentration of 1 x 10(-7) M of either agent. TAN but not BAN when administered systematically to mice produced an antinociceptive effect as measured by the writhing test. When administered intracerebraventricularly BAN did not block morphine-induced analgesia for more than 2 hr; whereas, with a single ED50 dose of 20 nmoles of TAN i.c.v. morphine-induced analgesia was almost completely blocked for a period of over 24 hr, as determined by the tail flick test. Although the SH group of TAN were required for the covalent interaction with opioid receptors, the site of TAN's interaction appears to involve other than protein SH groups.