Bioactivity Of Opioidmimetic Substances

工作总结：在小鼠体内测定了最近开发的类阿片物质对这种活性的抗伤害性和拮抗剂，并与吗啡(Mu-阿片受体激动剂)和Deltorpin(增量-阿片激动剂)进行了比较，以评估它们的作用模式。抗伤害性数据与体外功能药理数据GPI(豚鼠回肠)和MVD(小鼠输精管)相似，并反映了阿片受体结合亲和力(有关化合物与β阿片受体和Mu阿片受体相互作用的详细信息，见项目1)。一系列新型DMT-Tic药物或原药物在体内外表现出拮抗作用，采用热板法(脊髓上效应)和甩尾试验(脊髓效应)。对照化合物具有中枢(CNS)介导的镇痛作用，是口服生物利用型阿片类药物。 有趣的是，N，N-二甲基-DMT-Tic-NH-金刚烷和叔丁基衍生物抑制了小鼠对吗啡的耐受性，提示多药耐药P-糖蛋白1可能与这些阿片类似物在体外对PG-1的抑制有关。其他DMT-Tic化合物，特别是MZ-2(专利申请正在申请中)可防止形成对吗啡和烯丙化内吗啡的耐受性，但相反，它作为双重拮抗剂同时抑制β-阿片和u-阿片活性。此外，耐受性的消除没有纳洛酮和纳曲酮所见的严重副作用。 对内吗啡-1和-2中含有DMT而不是Tyr的MU阿片激动剂的研究表明，它们的作用模式不同，这也有助于区分这些结构相关的化合物。虽然两种化合物都有很强的镇痛作用，但它们的作用方式和镇痛程度明显不同。在体外和体内，DMT使所有测量的活度参数增加了几个数量级。两种内吗啡的N-烯丙基衍生物都是有效的Mu阿片拮抗剂，小鼠脑室给药证明：它们有效地抑制吗啡的抗伤害作用，类似于纳洛酮。

Summary of Work: Antinociception and antagonists to this activity by recently developed opioidmimetic substances was determined in vivo in mice in comparison to morphine (mu-opioid receptor agonist) and deltorpin (delta-opioid agonist) to assess their mode of action. The antinociception profile paralleled that of the in vitro functional pharmacological data GPI (guinea-pig ileum) and MVD (mouse vas deferens) and reflected the opioid-receptor binding affinity (see, Project 1 for details on the interaction of compounds with delta- and mu-opioid receptors). A series of novel Dmt-Tic pharmacophoric drugs or protodrugs exhibited antagonism in vitro and in vivo using the hot-plate (supraspinal effects, the central nervous system) and tail-flick test (spinal effects). The control compounds exhibited central (CNS) mediated analgesia and were orally bioavailable opioidmimetics. Interestingly, the N,N-dimethyl-Dmt-Tic-NH-adamantane and -tert-butyl derivatives inhibited tolerance to morphine in mice, which suggests that the multidrug resistance P-glycoprotein 1 was involved in this observation due to the inhibition in vitro of Pg-1 by these opioid analogues. Other Dmt-Tic compounds, MZ-2, in particular (patent application pending) prevents the formation of tolerance to morphine and like the allylated endomorphines (infra vide), but in contrast act as dual antagonists to inhibit both delta- and mu-opioid activities. Furthermore, the elimination of tolerance occurred without the severe side-effects seen with both naloxone and naltrexone. Studies on the mu opioid agonists containing Dmt in lieu of Tyr in endomorphins-1 and -2 revealed differences in their mode of action that also serve to differential these stucturally related compounds. Whereas both compounds exhibited potent analgesia, their mode of action and degree of analgesia was significantly different. Dmt enhanced all measured parameters of activity by orders of magnitude both in vitro and in vivo. The N-allyl derivatives of both endomorphines were potent mu-opioid antagonists as demonstrated by intracerebroventricular administration in mice: they effectively inhibited morphine antinociception similar to naloxone.