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.

Han C, Chatterjee A, Noetzel MJ, Panarese JD, Smith E, Chase P, Hodder P, Niswender C, Conn PJ, Lindsley CW, Stauffer SR
Bioorg Med Chem Lett. 2015 25 (2): 384-8

PMID: 25435150 · PMCID: PMC4278958 · DOI:10.1016/j.bmcl.2014.11.011

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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MeSH Terms (13)

Allosteric Regulation Allosteric Site Drug Discovery Humans Models, Molecular Molecular Docking Simulation Molecular Structure Pyrazoles Quinolines Quinolones Receptor, Muscarinic M1 Small Molecule Libraries Structure-Activity Relationship

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