4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor.

Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer's and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.

[1]  J. Wess,et al.  Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice. , 2015, ACS chemical neuroscience.

[2]  J. Canon,et al.  Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres. , 2014, Journal of medicinal chemistry.

[3]  S. Kuduk,et al.  Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators. , 2014, Bioorganic & medicinal chemistry letters.

[4]  P. Sexton,et al.  Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor. , 2013, Journal of medicinal chemistry.

[5]  Shailesh N Mistry,et al.  Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor. , 2013, Journal of medicinal chemistry.

[6]  A. Christopoulos,et al.  Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. , 2013, ACS chemical neuroscience.

[7]  M. Foster Olive,et al.  Novel Allosteric Agonists of M1 Muscarinic Acetylcholine Receptors Induce Brain Region-Specific Responses That Correspond with Behavioral Effects in Animal Models , 2012, The Journal of Neuroscience.

[8]  P. Sexton,et al.  A Monod-Wyman-Changeux Mechanism Can Explain G Protein-coupled Receptor (GPCR) Allosteric Modulation* , 2011, The Journal of Biological Chemistry.

[9]  S. Hitchcock,et al.  Pharmacological Characterization of LY593093, an M1 Muscarinic Acetylcholine Receptor-Selective Partial Orthosteric Agonist , 2011, Journal of Pharmacology and Experimental Therapeutics.

[10]  Frank M LaFerla,et al.  Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline. , 2011, The American journal of pathology.

[11]  N. Meanwell.  Synopsis of some recent tactical application of bioisosteres in drug design. , 2011, Journal of medicinal chemistry.

[12]  Serge Gauthier,et al.  Update on the Pharmacological Treatment of Alzheimer’s Disease , 2010, Current neuropharmacology.

[13]  K. Mcfarland,et al.  AC-260584, an orally bioavailable M1 muscarinic receptor allosteric agonist, improves cognitive performance in an animal model , 2010, Neuropharmacology.

[14]  S. B. Caine,et al.  Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice , 2010, Psychopharmacology.

[15]  W. Shipe,et al.  Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M(1) positive allosteric modulators. , 2010, Bioorganic & medicinal chemistry letters.

[16]  M. Quirk,et al.  A Selective Allosteric Potentiator of the M1 Muscarinic Acetylcholine Receptor Increases Activity of Medial Prefrontal Cortical Neurons and Restores Impairments in Reversal Learning , 2009, The Journal of Neuroscience.

[17]  Craig W. Lindsley,et al.  Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation , 2009, Proceedings of the National Academy of Sciences.

[18]  C. Lindsley,et al.  Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. , 2009, Trends in pharmacological sciences.

[19]  B. Dean,et al.  Muscarinic receptors: do they have a role in the pathology and treatment of schizophrenia? , 2008, Journal of neurochemistry.

[20]  A. Deutch,et al.  Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats , 2008, The Journal of Neuroscience.

[21]  Craig Mallinckrodt,et al.  Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. , 2008, The American journal of psychiatry.

[22]  M. Whittington,et al.  Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77‐LH‐28‐1 , 2008, British journal of pharmacology.

[23]  Christopher J Langmead,et al.  Muscarinic acetylcholine receptors as CNS drug targets. , 2008, Pharmacology & therapeutics.

[24]  P. Sexton,et al.  Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. , 2007, Trends in pharmacological sciences.

[25]  D. Ogg,et al.  Investigation of potential bioisosteric replacements for the carboxyl groups of peptidomimetic inhibitors of protein tyrosine phosphatase 1B: identification of a tetrazole-containing inhibitor with cellular activity. , 2002, Journal of medicinal chemistry.

[26]  B. Craven,et al.  Charge density study of 2-pyridone. , 1998, Acta crystallographica. Section B, Structural science.

[27]  A. Christopoulos.  Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log. , 1998, Trends in pharmacological sciences.

[28]  W W Offen,et al.  Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. , 1997, Archives of neurology.

[29]  B. D. Harris,et al.  Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures(1). , 1996, The Journal of organic chemistry.

[30]  B. Penfold.  The electron distribution in crystalline α-pyridone , 1953 .

[31]  Shailesh N Mistry,et al.  Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor. , 2017 .

[32]  C. Lindsley,et al.  Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model , 2016, Neuropsychopharmacology.

[33]  N. Pomara.  Reduction in muscarinic M1-mediated hypercholinergic state and beneficial cognitive effects of muscarinic agonists in schizophrenia. , 2009, The American journal of psychiatry.

[34]  Arthur Christopoulos,et al.  Allosteric modulation of G protein-coupled receptors. , 2007, Annual review of pharmacology and toxicology.

[35]  Alcino J. Silva,et al.  Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice , 2003, Nature Neuroscience.

[36]  B. Dean,et al.  Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia , 2002, Molecular Psychiatry.

[37]  D. Aksnes,et al.  Substituent and Solvent Effects in the Proton Magnetic Resonance (PMR) Spectra of Six 2-Substituted Pyridines. , 1972 .