Bi- or multifunctional opioid peptide drugs.
Bi- or multifunctional opioid peptide drugs.
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DOI：
10.1016/j.lfs.2009.02.025
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发表时间：
2010-04-10
期刊：
影响因子：
6.1
通讯作者：
Schiller, Peter W.
中科院分区：
文献类型：
--
作者：
Schiller, Peter W.
综述了双功能或多功能药物的设计策略。双功能药物以单价方式与两个靶点相互作用，配体含有两种不同的药物载体，以二价方式与受体异二聚体中的两个结合位点结合。提出的论点表明，在文献中报道的一些所谓的“二价”配体不太可能同时与两个结合位点相互作用。从阿片类镇痛药领域的例子说明了与双功能或多功能药物发展有关的方面。本文综述了四肽Dmt1[DALDA]作为μ阿片受体激动剂、去甲肾上腺素摄取抑制剂和内源性阿片肽释放剂产生强效脊髓镇痛的药物样特性。开发阿片肽混合激动剂/拮抗剂的基本原理，作为镇痛药与减少副作用提出。综述了低耐受性和身体依赖性的混合μ阿片受体激动剂/δ阿片受体拮抗剂的研究进展。本文还综述了开发含有μ阿片受体激动剂和胆囊收缩素拮抗剂或NK1受体拮抗剂的双功能肽作为镇痛药的研究进展，以期产生较少的耐受性和依赖性。提出了一种改善双功能阿片肽镇痛药类药物特性的策略。
Strategies for the design of bi- or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called “bivalent” ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi- or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt1[DALDA] with triple action as a μ opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed μ opioid agonist/δ opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a μ opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented.
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影响因子：
3.8
作者：
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