Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-D-Pro-Phe-Trp] (CJ-15,208)
Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-D-Pro-Phe-Trp] (CJ-15,208)
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DOI：
10.1021/acs.jmedchem.6b00420
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发表时间：
2016-10-13
影响因子：
7.3
通讯作者：
Gentilucci, Luca
中科院分区：
文献类型：
--
作者：
De Marco, Rossella;Bedini, Andrea;Gentilucci, Luca
最近，出现了含有色氨酸、不可阳离子化的阿片肽，其具有非典型结构和意想不到的体内活性。在此，我们描述了天然存在的混合 x/mu-配体 c[Phe-b-Pro-Phe-Trp] 1 (CJ-15,208) 的类似物。受体亲和力、选择性和。激动/拮抗作用随着大环尺寸的增大而变化，产生具有低纳摩尔亲和力特征的μ激动剂9或δ拮抗剂10。特别是，mu 激动剂 c[β-Ala-D-Pro-Phe-Trp]9 在全身给药的内脏疼痛小鼠模型中显示出有效的镇痛作用。
Recently, the tryptophan-containing,noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed x/mu-ligand c[Phe-b-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and. agonism/ antagonism varied upon enlarging macrocycle size, giving the mu-agonist 9 or the delta-antagonist 10 characterized by low nanomolar affinity. In particular, the mu-agonist c[beta-Ala-D-Pro- Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.