PHARMACOLOGICAL PROFILE OF NPC-168 (NALTREXONE PHENYL OXIME), A NOVEL COMPOUND WITH ACTIVITY AT OPIOID RECEPTORS
PHARMACOLOGICAL PROFILE OF NPC-168 (NALTREXONE PHENYL OXIME), A NOVEL COMPOUND WITH ACTIVITY AT OPIOID RECEPTORS
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DOI：
10.1016/0091-3057(90)90019-e
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发表时间：
1990-11-01
影响因子：
3.6
通讯作者：
STERANKA, LR
中科院分区：
文献类型：
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作者：
DEHAVENHUDKINS, DL;BROSTROM, PA;STERANKA, LR
NPC 168（纳曲酮苯基肟）作为新型阿片拮抗剂合成，并通过多项体外和体内测定进行评估。 NPC 168抑制与μ、s和κ的结合。具有纳摩尔效力的阿片受体亚型。腹膜内（ED50 = 0.07 mg/kg）或口服（ED50 = 0.82 mg/kg）给药后，NPX 168 拮抗吗啡诱导镇痛的效力略低于纳曲酮和纳美芬。皮下给药后，NPC 168 的作用持续时间约为 8 小时，而纳美芬为 4 小时，以拮抗羟吗啉诱导的镇痛作用。药代动力学数据证实了 NPC 168 的长作用持续时间，该数据表明 NPC 168 从大脑中快速摄取并缓慢清除。 NPC 168（5、10 和 20 mg/kg）还抑制了 24 小时禁食的大鼠的 6 小时累积食物摄入量，但在三周内长期给大鼠施用该化合物导致累积体重增加略有减少。 NPC 168 在剂量高达 10 mg/kg 时不会产生条件性味觉厌恶。因此，当肠胃外给药时，NPC 168 的毒性比纳曲酮或纳美芬稍高，而当口服途径给药时，毒性与纳美芬相同。这些数据表明 NPC 168 是一种新型阿片拮抗剂，其作用持续时间比早期的纳曲酮或纳美芬更长。
NPC 168 (naltrexone phenyl oxime) was synthesized as a nvel opoid antagonist and evaluate din several in vitro and in vivo assays. NPC 168 inhibited binding to tthe .mu., s and .kappa. subtypes of the opioid receptor with nanomolar potencies. The potency of NPX 168 to antagonize morphine-induced analgesia was slightly less than that of naltrexone and nalmefene following either intraperitoneal (ED50 = 0.07 mg/kg) or oral (ED50 = 0.82 mg/kg) administration. The duration of ation of NPC 168 was approximately 8 hr following subcutaneous administratino, compared to 4 hr for nalmefene, to antagonize oxymorphoanize-induce analgesia. The long duration of action of NPC 168 was substantiated by pharmacokinetic data that demonstrated rapid uptake and slow clearance of NPC 168 from brain. NPC 168 (5, 10 and 20 mg/kg) also inhibited cumulative 6-hr food intake in rats that were deprived of food for 24 hr, bur chronic administered of this compound to rats over a three-week period resulted in a marginal reduction in cumulative body weight gain. NPC 168 at doses of up to 10 mg/kg did not produce a conditioned taste aversion. Hence, NPC 168 was slightly more toxic than either naltrexone or nalmefene when administered parenterally, and as toxic as nalmenfene when administered by the oral route. These data demonstrate that NPC 168 is a novel opioid antagonist with a longer duration of action than earlier naltrexone or nalmefene.