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

Changho Han; Arindam Chatterjee; Meredith J Noetzel; Joseph D Panarese; Emery Smith; Peter Chase; Peter Hodder; Colleen Niswender; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer

doi:10.1016/j.bmcl.2014.11.011

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

Bioorg Med Chem Lett. 2015 Jan 15;25(2):384-8. doi: 10.1016/j.bmcl.2014.11.011. Epub 2014 Nov 18.

Affiliations

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
² The Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.
³ Amgen Inc., Thousand Oaks, California, USA.
⁴ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: shaun.stauffer@vanderbilt.edu.

Abstract

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.

Keywords: M(1); Muscarinic receptor 1; Positive allosteric modulator (PAM); mAChR.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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

Substances

CID 915409
Pyrazoles
Quinolines
Quinolones
Receptor, Muscarinic M1
Small Molecule Libraries

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding