Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego Street 5, 02106 Warsaw, Poland.
Mol Pain. 2010 Dec 6;6:86. doi: 10.1186/1744-8069-6-86.
The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor.
Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia.
The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.
各种类型的疼痛的临床治疗依赖于阿片类镇痛药的使用。然而，除了镇痛作用外，它们大多数还会产生一些副作用，如依赖和成瘾以及镇静、不适和便秘。解决这些问题的一种方法是使用嵌合化合物，其中阿片类药效团与另一种化合物杂交，以增加抗伤害效应。神经降压素诱导的镇痛作用不是通过阿片系统介导的。因此，将神经降压素与阿片类元素杂交可能会产生一种有效的协同抗伤害剂。
利用已知的神经降压素结构-活性关系，我们合成了一种新的阿片类-神经降压素嵌合化合物 PK20，其具有很强的镇痛作用。阿片类拮抗剂纳曲酮不能完全逆转镇痛作用的观察表明，非阿片类成分在 PK20 产生的镇痛作用中部分参与。
阿片类-神经降压素混合类似物 PK20 中，阿片类和神经降压素药效团部分重叠，在中枢和外周应用后均表现出高尾部闪烁效应。
