MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys.
MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys.
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DOI：
10.1155/2012/327257
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发表时间：
2012
影响因子：
--
通讯作者：
Portoghese PS
中科院分区：
文献类型：
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作者：
Aceto MD;Harris LS;Negus SS;Banks ML;Hughes LD;Akgün E;Portoghese PS
MDAN-21, 7′-{2-[(7-{2-[({(5α, 6α)-4,5-环氧-3,14-二羟基-17-甲基吗啡-6-基}-氨基羰基)甲氧基]-乙酰氨基}-庚氨基羰基)-甲氧基]-乙酰氨基}-纳曲吲哚，一种含有 mu-阿片受体激动剂的二价阿片配体（源自据报道，羟吗啡酮通过 21 个原子的间隔基与 δ-阿片受体拮抗剂（与纳曲吲哚有关）连接，对小鼠具有有效的镇痛作用。该物种的耐受性、身体依赖性和条件性位置偏好并不明显。该系列中具有 19 个或更多原子间隔的二价配体缺乏耐受性和依赖性，这一发现导致有人提出 MDAN-21 靶向异聚 mu-δ-阿片受体。目前的研究重点是它对非人类灵长类动物（Macaca mulatta）的影响，这种动物的生理和行为能力与人类没有什么不同。对于阿片类药物，该物种通常可以更好地预测临床结果。 MDAN-21 在吗啡依赖性猴子中以 0.006–0.032mg/kg 的极低剂量范围（皮下注射）替代吗啡。尽管MDAN-21在0.0032-0.032mg/kg的剂量范围内未能产生可靠的热镇痛作用，但在辣椒素诱导的热异常性疼痛测定中，它在相同的剂量范围和相同的给药途径下具有活性。结果表明 MDAN-21 可用于治疗阿片类药物依赖和异常性疼痛。这些数据提供了额外的证据表明阿片类药物戒断与过敏性疼痛有关。
MDAN-21, 7′-{2-[(7-{2-[({(5α, 6α)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006–0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032–0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain.