Modifications of the cyclic mu receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et): effects on opioid receptor binding and activation.
Modifications of the cyclic mu receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et): effects on opioid receptor binding and activation.
复制标题
环状 mu 受体选择性四肽 Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et) 的修饰：对阿片受体结合和激活的影响。
DOI：
10.1034/j.1399-3011.2000.00177.x
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Traynor,JR
中科院分区：
文献类型：
--
作者：
McFadyen,IJ;Ho,JC;Mosberg,HI;Traynor,JR
先前描述的环状μ阿片受体选择性四肽Tyr-c[d-Cys-Phe-d-Pen]NH2(Et) (JOM-6)通过用各种天然和合成氨基酸取代和/或通过改变循环系统在残基1和3处进行修饰。评估了对 mu 和 delta 阿片受体结合亲和力的影响，以及对通过 [35S]-GTPγS 测定测量的效力和功效的影响。用构象限制的酚氨基酸取代 Tyr1 不会显着影响 mu 和 delta 受体的亲和力。在 [35S]-GTPγS 测定中，所有测试的肽都在 mu 阿片受体上表现出与芬太尼相当的最大反应，并且都在 0.4–9 nm 范围内表现出高效力。然而，效力变化并不总是与亲和力相关，这表明结合所需的构象和阿片受体激活所需的构象是不同的。对于 δ 阿片受体，没有一种肽能够产生与完全 δ 激动剂 BW 373,U86 相当的反应，并且只有一种肽的 EC50 值小于 100nm。最后，我们鉴定了一种肽，d-Hat-c[d-Cys-Phe-d-Pen]NH2(Et)，通过[35S]-GTPγS测定测量，它对μ超过δ阿片受体具有高效力和> 1000倍的功能选择性。
The previously described cyclic mu opioid receptor‐selective tetrapeptide Tyr‐c[d‐Cys‐Phe‐d‐Pen]NH2(Et) (JOM‐6) was modified at residues 1 and 3 by substitution with various natural and synthetic amino acids, and/or by alteration of the cyclic system. Effects on mu and delta opioid receptor binding affinities, and on potencies and efficacies as measured by the [35S]‐GTPγS assay, were evaluated. Affinities at mu and delta receptors were not influenced dramatically by substitution of Tyr1with conformationally restricted phenolic amino acids. In the [35S]‐GTPγS assay, all of the peptides tested exhibited a maximal response comparable with that of fentanyl at the mu opioid receptor, and all showed high potency, in the range0.4–9 nm. However, potency changes did not always correlate with affinity, suggesting that the conformation required for binding and the conformation required for activation of the opioid receptors are different. At the delta opioid receptor, none of the peptides were able to produce a response equivalent to that of the full delta agonist BW 373,U86 and only one had an EC50value of less than 100 nm. Lastly, we have identified a peptide,d‐Hat‐c[d‐Cys‐Phe‐d‐Pen]NH2(Et), with high potency and > 1000‐fold functional selectivity for the mu over delta opioid receptor as measured by the [35S]‐GTPγS assay.
登录
查看更多内容
DOI：
10.1073/pnas.80.19.5871
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
MOSBERG, HI;HURST, R;BURKS, TF
通讯作者：
BURKS, TF
影响因子：
3.6
作者：
Mosberg,HI;Omnaas,JR;Goldstein,A
通讯作者：
Goldstein,A
影响因子：
7.3
作者：
Mosberg,HI;Omnaas,JR;Lomize,A;Heyl,DL;Nordan,I;Mousigian,C;Davis,P;Porreca,F
通讯作者：
Porreca,F
影响因子：
7.3
作者：
Mosberg,HI;Lomize,AL;Wang,C;Kroona,H;Heyl,DL;Sobczyk-Kojiro,K;Ma,W;Mousigian,C;Porreca,F
通讯作者：
Porreca,F
影响因子：
5
作者：
CLARK, MJ;CARTER, BD;MEDZIHRADSKY, F
通讯作者：
MEDZIHRADSKY, F