Hubbard J W, Locke K W, Forster H V, Brice A G, Pan L G, Lowry T F, Forster A M, Forster M A, Cornfeldt M, Vanselous C L
Department of Biological Research, Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey.
J Pharmacol Exp Ther. 1992 Mar;260(3):1268-77.
7-Bromo-(3a,5-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-pyrrolo[2,3- 6]indol-5-ol fumarate (HP 736) is a novel opioid analgesic. In vitro, HP 736 displaces [3H]dihydromorphine (IC50 = 8.3 x 10(-10) M) and [3H]bremazocine (IC50 = 7.4 x 10(-8) M) from mu and kappa opioid receptors, respectively, and displays modest acetylcholinesterase inhibitory activity (IC50 = 4.0 x 10(-5) M). The in vivo antinociceptive activity of HP 736 was found to be comparable to morphine in the modified Haffner's tail clip assay in mice and the D'Amour-Smith tail flick assay in rats. Moreover, these analgesic effects were found to be completely antagonized by the administration of the narcotic antagonist naloxone. A major liability of opioid analgesics such as morphine is the potential to cause cardiorespiratory depression. HP 736 (2, 4 and 10 mg/kg, i.v.) was found to cause significantly less respiratory depression in the anesthetized dog when compared to equivalent doses of morphine. At 10 mg/kg, morphine caused a 48% reduction in arterial oxygen partial pressure (PaO2) (-42.3 +/- 2.5 mm Hg) and a 52% increase in arterial carbon dioxide partial pressure (PaCO2) (21.0 +/- 3.4 mm Hg). In contrast, the same dose of HP 736 produced no significant decrease in PaO2, but did cause a slight 19% increase in PaCO2 (8.2 +/- 1.3 mm Hg), which was significantly less than the response seen after morphine treatment. It was found that pretreatment of the dogs with atropine sulfate (1 mg/kg, i.v.) "unmasked" the respiratory depressant activity of HP 736 (2 mg/kg, i.v.), indicating that the acetylcholinesterase inhibitory activity of the compound may contribute to its reduced cardiorespiratory liability. Finally, in confirmatory experiments conducted in conscious goats, HP 736 (0.5 mg/kg, i.v.) was found to stimulate pulmonary ventilation, increase PaO2 and oxygen consumption (+40%) and decrease PaCO2 with an overall stimulatory effect on the metabolic rate. In contrast, the same dose of morphine decreased metabolic rate, reduced pulmonary ventilation (-20%) and PaO2 and increased PaCO2. Overall, the results of these studies indicate that HP 736 is a potent opioid analgesic which appears to lack significant cardiorespiratory depressant activity.
7-溴-(3a,5-顺式)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基-吡咯并[2,3-b]吲哚-5-醇富马酸盐（HP 736）是一种新型阿片类镇痛药。在体外，HP 736分别从μ和κ阿片受体上取代[3H]二氢吗啡（IC50 = 8.3×10(-10) M）和[3H]布瑞马唑辛（IC50 = 7.4×10(-8) M），并表现出适度的乙酰胆碱酯酶抑制活性（IC50 = 4.0×10(-5) M）。在小鼠改良的哈夫纳尾部夹捏试验和大鼠的达莫尔-史密斯甩尾试验中，发现HP 736的体内抗伤害感受活性与吗啡相当。此外，发现这些镇痛作用可被麻醉性拮抗剂纳洛酮完全拮抗。吗啡等阿片类镇痛药的一个主要缺点是有导致心肺抑制的可能性。与等效剂量的吗啡相比，发现HP 736（2、4和10 mg/kg，静脉注射）在麻醉犬中引起的呼吸抑制明显较少。在10 mg/kg时，吗啡使动脉血氧分压（PaO2）降低48%（-42.3±2.5 mmHg），动脉血二氧化碳分压（PaCO2）升高52%（21.0±3.4 mmHg）。相比之下，相同剂量的HP 736并未使PaO2显著降低，但确实使PaCO2略有升高19%（8.2±1.3 mmHg），这明显低于吗啡治疗后的反应。发现用硫酸阿托品（1 mg/kg，静脉注射）对犬进行预处理会“揭示”HP 736（2 mg/kg，静脉注射）的呼吸抑制活性，表明该化合物的乙酰胆碱酯酶抑制活性可能有助于其降低的心肺不良反应。最后，在清醒山羊中进行的验证性实验中，发现HP 736（0.5 mg/kg，静脉注射）可刺激肺通气，增加PaO2和氧消耗（+40%）并降低PaCO2，对代谢率有总体刺激作用。相比之下，相同剂量的吗啡降低代谢率，减少肺通气（-20%）和PaO2并增加PaCO2。总体而言，这些研究结果表明HP 736是一种强效阿片类镇痛药，似乎缺乏明显的心肺抑制活性。
