کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10595881 | 981877 | 2013 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Discovery of ML326: The first sub-micromolar, selective M5 PAM
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10 μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409 nM and 500 nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30 μM) and a robust 20-fold leftward shift of the ACh CRC.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 10, 15 May 2013, Pages 2996-3000
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 10, 15 May 2013, Pages 2996-3000
نویسندگان
Patrick R. Gentry, Thomas M. Bridges, Atin Lamsal, Paige N. Vinson, Emery Smith, Peter Chase, Peter S. Hodder, Julie L. Engers, Colleen M. Niswender, J. Scott Daniels, P. Jeffrey Conn, Michael R. Wood, Craig W. Lindsley,