3-O-acetylmorphine-6-O-sulfate: A potent, centrally acting morphine derivative
3-O-acetylmorphine-6-O-sulfate: A potent, centrally acting morphine derivative
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DOI：
10.1016/0091-3057(95)02067-5
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发表时间：
1996-03-01
影响因子：
3.6
通讯作者：
Butterfield, DA
中科院分区：
文献类型：
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作者：
Houdi, AA;Kottayil, S;Butterfield, DA
鉴于吗啡的结构明显不同的吗啡-6-O-葡萄糖醛酸苷(M6G)和吗啡-6-O-硫酸酯(M6S)结合物具有明显的镇痛作用，我们用甩尾实验研究了M6S的结构修饰对镇痛活性的影响。M6S的结构发生了变化，这将影响分子的亲脂性和极性。皮下(Sc)和脑室(Icv)注射等摩尔剂量的吗啡、M6S、3-O-乙酰吗啡-6-O-硫酸盐(M3A6S)、3-O-苯甲酰吗啡-6-O-硫酸盐(M3B6S)和3-O-乙酰基-N-甲基吗啡-6-O-硫酸盐(MM3A6S)。与吗啡相比，SC和icv给药后，M6s和M3A6s表现出更长的作用时间和更强的活性。然而，SC和icv给药后，等摩尔剂量的M3B6S和MM3A6S被发现是无效的。此外，M3A6S对电刺激豚鼠回肠的抑制作用最强，其次是M6S和M3B6S。此外，M6s和M3A6s对豚鼠脑匀浆中的Mu和Kappa受体部位的亲和力均高于吗啡。与吗啡相比，非镇痛化合物M3B6S和MM3A6S的受体结合能力较弱。这些结果表明，亲脂性本身并不是这些新型吗啡衍生物的止痛活性的决定因素。吗啡3位和6位结合的这些修饰效应，似乎是由于它们与阿片受体相互作用的改变所致。
In view of the potent analgesia exhibited by the apparent structurally dissimilar morphine-6-O-glucuronide (M6G) and morphine-6-O-sulfate (M6S) conjugates of morphine, we have examined the effect of structural modification of M6S on analgesic activity, using the tail-flick test. Changes in the M6S structure were made that would affect the lipophilicity and polarity of the molecule. Subcutaneous (sc) and intracerebroventricular (ICV) administration of equimolar doses of morphine, M6S, 3-O-acetylmorphine-6-O-sulfate (M3A6S), 3-O-benzoylmorphine-6-O-sulfate (M3B6S), and 3-O-acetyl-N-methylmorphinium-6-O-sulfate (MM3A6S) were employed. M6S and M3A6S exhibited a longer duration of action and greater activity compared to morphine after SC and ICV administration. However, M3B6S and MM3A6S in doses equimolar to that of morphine were found to be inactive after both SC and ICV administration. In addition, M3A6S showed the highest potency in inhibiting electrically stimulated guinea pig ileum followed by M6S and M3B6S. Moreover, both M6S and M3A6S displayed a greater affinity than that of morphine to mu and kappa, receptor sites in guinea pig brain homogenate. In contrast, the nonanalgesic compounds M3B6S and MM3A6S showed weak receptor binding ability compared to morphine. These results indicate that lipophilicity alone is not a determinant of analgesic activity in these novel morphine derivatives. These modified effects of morphine by the conjugations at the 3- and 6-position, appear to be due to their altered interactions with opioid receptors.