Grinnell Steven G, Majumdar Susruta, Narayan Ankita, Le Rouzic Valerie, Ansonoff Michael, Pintar John E, Pasternak Gavril W
Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.)
J Pharmacol Exp Ther. 2014 Sep;350(3):710-8. doi: 10.1124/jpet.114.213199. Epub 2014 Jun 26.
IBNtxA (3'-iodobenzoyl-6β-naltrexamide) is a potent analgesic in mice lacking many traditional opioid side effects. In mice, it displays no respiratory depression, does not produce physical dependence with chronic administration, and shows no cross-tolerance to morphine. It has limited effects on gastrointestinal transit and shows no reward behavior. Biochemical studies indicate its actions are mediated through a set of μ-opioid receptor clone MOR-1 splice variants associated with exon 11 that lack exon 1 and contain only six transmembrane domains. Like the mouse and human, rats express exon 11-associated splice variants that also contain only six transmembrane domains, raising the question of whether IBNtxA would have a similar pharmacologic profile in rats. When given systemically, IBNtxA is a potent analgesic in rats, with an ED50 value of 0.89 mg/kg s.c., approximately 4-fold more potent than morphine. It shows no analgesic cross-tolerance in morphine-pelleted rats. IBNtxA displays no respiratory depression as measured by blood oxygen saturation. In contrast, oximetry shows that an equianalgesic dose of morphine lowers blood oxygen saturation values by 30%. IBNtxA binding is present in a number of brain regions, with the thalamus standing out with very high levels and the cerebellum with low levels. As in mice, IBNtxA is a potent analgesic in rats with a favorable pharmacologic profile and reduced side effects.
IBNtxA（3'-碘苯甲酰基-6β-纳曲酰胺）在缺乏许多传统阿片类药物副作用的小鼠中是一种强效镇痛药。在小鼠中，它不会引起呼吸抑制，长期给药不会产生身体依赖性，并且对吗啡没有交叉耐受性。它对胃肠蠕动的影响有限，也不会表现出奖赏行为。生化研究表明，其作用是通过一组与外显子11相关的μ-阿片受体克隆MOR-1剪接变体介导的，这些变体缺乏外显子1，仅包含六个跨膜结构域。与小鼠和人类一样，大鼠也表达与外显子11相关的剪接变体，这些变体也仅包含六个跨膜结构域，这就提出了一个问题，即IBNtxA在大鼠中是否会有类似的药理学特征。全身给药时，IBNtxA在大鼠中是一种强效镇痛药，皮下注射的ED50值为0.89 mg/kg，效力约为吗啡的4倍。在植入吗啡丸的大鼠中，它没有表现出镇痛交叉耐受性。通过血氧饱和度测量，IBNtxA不会引起呼吸抑制。相比之下，血氧测定显示，等效镇痛剂量的吗啡会使血氧饱和度值降低30%。IBNtxA在多个脑区都有结合，丘脑的结合水平非常高，而小脑的结合水平较低。与在小鼠中一样，IBNtxA在大鼠中是一种强效镇痛药，具有良好的药理学特征且副作用减少。
