Design, synthesis, and pharmacological activities of dynorphin A analogues cyclized by ring-closing metathesis.
Design, synthesis, and pharmacological activities of dynorphin A analogues cyclized by ring-closing metathesis.
复制标题
DOI：
10.1021/jm900577k
复制
发表时间：
2009-09-24
影响因子：
7.3
通讯作者：
Aldrich JV
中科院分区：
文献类型：
--
作者：
Fang WJ;Cui Y;Murray TF;Aldrich JV
强啡肽A（DynA）是κ阿片受体的内源性配体。为了限制构象迁移率，我们在固相上合成了几种环状Dyn A-（1-11）NH 2类似物，其利用在位置2、5和/或8中掺入的烯丙基甘氨酸（AllGly）残基的侧链之间的闭环复分解（RCM）。AllGly的侧链之间的环化给出了所有所需环肽的合理产率（56-74%）。顺式和反式异构体都获得了所有的环肽，顺式与反式异构体的比例取决于AllGly的位置和立体化学。所检测的大多数环状Dyn A-（1-11）NH 2类似物对κ阿片受体表现出低纳摩尔结合亲和力（Ki = 0.84-11 nM）。在三种情况中的两种情况下，双键的构型对阿片受体亲和力和激动剂效力具有显著影响。所有的肽抑制腺苷酸环化酶（AC）的活性在浓度依赖性的方式与完全或接近完全激动剂活性。这些有效的Dyn A类似物是第一个被RCM环化的类似物。
Dynorphin A (Dyn A) is an endogenous ligand for kappa (κ) opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogs on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5 and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56–74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogs examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84–11 nM). In two of the three cases the configuration of the double bond has a significant influence on the opioid receptor affinity and agonist potency. All of the peptides inhibited adenylyl cyclase (AC) activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogs are the first ones cyclized by RCM.
登录
查看更多内容
DOI：
10.1111/j.1399-3011.2005.00216.x
发表时间：
2005-03-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Bennett, MA;Murray, TF;Aldrich, JV
通讯作者：
Aldrich, JV
DOI：
10.1073/pnas.78.10.6543
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CHAVKIN, C;GOLDSTEIN, A
通讯作者：
GOLDSTEIN, A
影响因子：
56.9
作者：
FREIDINGER, RM;VEBER, DF;SAPERSTEIN, R
通讯作者：
SAPERSTEIN, R
影响因子：
7.3
作者：
Arttamangkul, S;Ishmael, JE;Aldrich, JV
通讯作者：
Aldrich, JV
影响因子：
7.3
作者：
Berezowska, Irena;Chung, Nga N.;Schiller, Peter W.
通讯作者：
Schiller, Peter W.