کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10596176 | 981897 | 2013 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Further exploration of M1 allosteric agonists: Subtle structural changes abolish M1 allosteric agonism and result in pan-mAChR orthosteric antagonism
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
This letter describes the further exploration of two series of M1 allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M1 allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M1 allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M1 activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 1, 1 January 2013, Pages 223-227
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 1, 1 January 2013, Pages 223-227
نویسندگان
Douglas J. Sheffler, Christian Sevel, Uyen Le, Kimberly M. Lovell, James C. Tarr, Sheridan J.S. Carrington, Hyekyung P. Cho, Gregory J. Digby, Colleen M. Niswender, P. Jeffrey Conn, Corey R. Hopkins, Michael R. Wood, Craig W. Lindsley,