کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1398667 1501105 2016 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues
چکیده انگلیسی


• A new series of TRH analogues was synthesized.
• Peptide 7k showed 925-fold selectivity towards mTRH-R2 receptor in the IP-1 assay.
• Peptide 7k showed 272-fold selectivity towards mTRH-R2 receptor in the FLIPR assay.
• Peptide 7k decreased the sleeping time by >76% in a PB-induced assay.

Thyrotropin-releasing hormone (TRH) analogues bearing halogen groups (Cl, Br and I) at the C-2 and/or C-5 position, and the alkyl group (CH3, C2H5, C3H7, CH2C6H5) at the N-1 position of the imidazole ring of the central histidine residue were synthesized and evaluated for the receptor binding, calcium mobilization (FLIPR), and IP-1 assay at the HEK mTRHR1 and HEK mTRHR2 expressing cell lines. The most promising analogue 7k showed 925-fold selectivity for HEK mTRH-R2 receptor subtype in the IP-1 assay, 272-fold selectivity for HEK mTRH-R2 receptor subtype in the FLIPR assay, and 21-fold receptor binding specificity at HEK TRH-R2 receptor subtype. The peptide 7k was evaluated in vitro in a brain membrane competitive binding assay, and for stability analysis in the presence of TRH-DE, in vivo. The analogue 7k showed decrease in the sleeping time by more than 76% in a pentobarbital-induced sleeping assay, and showed comparatively less elevation in the TSH level in the blood, in vivo. The computational homology modeling of TRH-R1 and TRH-R2 and docking study with the most potent peptide 7k provide impetus to design CNS specific TRH analogues.

Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 111, 23 March 2016, Pages 72–83
نویسندگان
, , , , , ,