کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5813765 | 1556616 | 2015 | 35 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting
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کلمات کلیدی
MORMouse striatumd-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2norBNICTOPGPCRnorbinaltorphimineDAMGO - DREAMG protein coupled receptor - G پروتئین همراه با پروتئین[35S]GTPγS - [35S] GTPγS[35S]GTPγS binding - [35S] اتصال GTPγSSelectivity - انتخابیDOR - دردdynorphin - دینورفینDyn - مردknock-out - ناک اوتwild-type - نوع وحشیKOR - وقتیDrug discovery - کشف مواد مخدرkappa opioid receptor - گیرنده اپوئیدی کاپاپMu opioid receptor - گیرنده اپیدمی مdelta opioid receptor - گیرنده دلتا اپیوئید
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Differential modulation of kappa opioid receptor (KOR) signaling has been a proposed strategy for developing therapies for drug addiction and depression by either activating or blocking this receptor. Hence, there have been significant efforts to generate ligands with diverse pharmacological properties including partial agonists, antagonists, allosteric modulators as well as ligands that selectively activate some pathways while not engaging others (biased agonists). It is becoming increasingly evident that G protein coupled receptor signaling events are context dependent and that what may occur in cell based assays may not be fully indicative of signaling events that occur in the naturally occurring environment. As new ligands are developed, it is important to assess their signaling capacity in relevant endogenous systems in comparison to the performance of endogenous agonists. Since KOR is considered the cognate receptor for dynorphin peptides we have evaluated the selectivity profiles of dynorphin peptides in wild-type (WT), KOR knockout (KOR-KO), and mu opioid receptor knockout (MOR-KO) mice using [35S]GTPγS binding assay in striatal membrane preparations. We find that while the small molecule KOR agonist U69,593, is very selective for KOR, dynorphin peptides promiscuously stimulate G protein signaling in striatum. Furthermore, our studies demonstrate that norBNI and 5â²GNTI are highly nonselective antagonists as they maintain full potency and efficacy against dynorphin signaling in the absence of KOR. Characterization of a new KOR antagonist, which may be more selective than NorBNI and 5â²GNTI, is presented using this approach.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 99, December 2015, Pages 131-141
Journal: Neuropharmacology - Volume 99, December 2015, Pages 131-141
نویسندگان
Lei Zhou, Edward L. Stahl, Kimberly M. Lovell, Kevin J. Frankowski, Thomas E. Prisinzano, Jeffrey Aubé, Laura M. Bohn,