期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 22, 页码 10291-10298出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01411
关键词
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资金
- U.S. Public Health Services, NIH
- NIDA [RO1 DA 13449, PO1 DA 006284]
Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the kappa opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg(7) residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg(7)]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg(7)]Dyn A-(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR. mediated disorders such as stress-induced relapse.
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