کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9001920 | 1118563 | 2005 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y13 receptor
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کلمات کلیدی
HRMSKrebs–Ringer–HEPESP2Y13 receptorKRHPPADSPLCIP3DMEMInositol trisphosphatePurinesFBSDulbecco's modified Eagle's medium - Medal of Eagle اصلاح شده DulbeccoCho - برایChinese Hamster Ovary - تخمدان هامستر چینیfetal bovine serum - سرم جنین گاوhigh-resolution mass spectrometry - طیف سنجی جرمی با وضوح بالاphospholipase C - فسفولیپاز CAdenine nucleotides - نوکلئوتید آدنین
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxal-5â²-phosphate-6-azo-phenyl-2,4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Y13 nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing Gα16 protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5â²-alkyl phosphonate analogues were synthesized and tested. A 6-benzyl-5â²-methyl phosphonate analogue was prepared to examine the effect of stable replacement of the azo linkage. The highest antagonistic potency was observed for 6-(3-nitrophenylazo) derivatives of pyridoxal-5â²-phosphate. The 2-chloro-5-nitro analogue (MRS 2211) and 4-chloro-3-nitro analogue (MRS 2603) inhibited ADP (100 nM)-induced inositol trisphosphate (IP3) formation with pIC50 values of 5.97 and 6.18, respectively, being 45- and 74-fold more potent than PPADS. The antagonism of MRS 2211 was competitive with a pA2 value of 6.3. MRS2211 and MRS2603 inhibited phospholipase C (PLC) responses to 30 nM 2-methylthio-ADP in human P2Y1 receptor-mediated 1321N1 astrocytoma cells with IC50 values of >10 and 0.245 μM, respectively. Both analogues were inactive (IC50 > 10 μM) as antagonists of human P2Y12 receptor-mediated PLC responses in 1321N1 astrocytoma cells. Thus, MRS2211 displayed >20-fold selectivity as antagonist of the P2Y13 receptor in comparison to P2Y1 and P2Y12 receptors, while MRS2603 antagonized both P2Y1 and P2Y13 receptors.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 70, Issue 2, 15 July 2005, Pages 266-274
Journal: Biochemical Pharmacology - Volume 70, Issue 2, 15 July 2005, Pages 266-274
نویسندگان
Yong-Chul Kim, Jung-Sun Lee, Katrin Sak, Frederic Marteau, Liaman Mamedova, Jean-Marie Boeynaems, Kenneth A. Jacobson,