Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators.
Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators.
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DOI：
10.1016/j.bmcl.2014.11.011
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发表时间：
2015-01-15
影响因子：
2.7
通讯作者：
Stauffer, Shaun R.
中科院分区：
文献类型：
--
作者：
Han, Changho;Chatterjee, Arindam;Noetzel, Meredith J.;Panarese, Joseph D.;Smith, Emery;Chase, Peter;Hodder, Peter;Niswender, Colleen;Conn, P. Jeffrey;Lindsley, Craig W.;Stauffer, Shaun R.
报道了NIH分子库小分子库（MLSMR）针对人类毒蕈碱受体亚型1（M1）的2012年高通量筛选阳性变构调节剂的结果。利用细胞内钙动员三重添加方案进行的内容丰富的筛选允许在单个筛选平台中评估M1的所有三种药理学模式，包括激动剂、正变构调节剂和拮抗剂活性。我们公开了二苄基-2H-吡唑并[4，3-c]喹啉-3（5 H）-酮（DBPQ，CID 915409），并检查了N-苄基药效团/SAR与先前报道的喹啉-3（5 H）-酮和靛红（包括ML 137）的关系。SAR和考虑最近报道的晶体结构，同源性建模，和结构-功能关系，使用点突变表明一个共享的结合模式取向在推定的共同变构结合位点的指导下的悬垂N-苄基亚结构。
Results from a 2012 high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) against the human muscarinic receptor subtype 1 (M1) for positive allosteric modulators is reported. A content-rich screen utilizing an intracellular calcium mobilization triple-addition protocol allowed for assessment of all three modes of pharmacology at M1, including agonist, positive allosteric modulator, and antagonist activities in a single screening platform. We disclose a dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one hit (DBPQ, CID 915409) and examine N-benzyl pharmacophore/SAR relationships versus previously reported quinolin-3(5H)-ones and isatins, including ML137. SAR and consideration of recently reported crystal structures, homology modeling, and structure-function relationships using point mutations suggests a shared binding mode orientation at the putative common allosteric binding site directed by the pendant N-benzyl substructure.
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影响因子：
4.2
作者：
Kuduk, Scott D.;Chang, Ronald K.;Bilodeau, Mark T.
通讯作者：
Bilodeau, Mark T.
影响因子：
2.7
作者：
Kuduk, Scott D.;DiPardo, Robert M.;Bilodeau, Mark T.
通讯作者：
Bilodeau, Mark T.
影响因子：
7.3
作者：
Kuduk, Scott D.;Chang, Ronald K.;Rays, William J.
通讯作者：
Rays, William J.
影响因子：
--
作者：
Bodick, NC;Offen, WW;Paul, SM
通讯作者：
Paul, SM
影响因子：
4.8
作者：
Abdul-Ridha, Alaa;Lopez, Laura;Christopoulos, Arthur
通讯作者：
Christopoulos, Arthur