Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M₁ Muscarinic Acetylcholine Receptor

Abstract

. (2016) Novel fused arylpyrimidinone based allosteric modulators of the M1 muscarinic acetylcholine receptor. ACS Chemical Neuroscience, 7 (5). pp. 647-661. ISSN 1948-7193 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/31897/1/acschemneuro%252E6b00018.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Just Accepted "Just Accepted" manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides "Just Accepted" as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. "Just Accepted" manuscripts appear in full in PDF format accompanied by an HTML abstract. "Just Accepted" manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). "Just Accepted" is an optional service offered to authors. Therefore, the "Just Accepted" Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the "Just Accepted" Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these "Just Accepted" manuscripts. ABSTRACT: Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M 1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M 1 mAChR.We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). ...

Probing the binding site of novel selective positive allosteric modulators at the M1 muscarinic acetylcholine receptor

“…Consistent with the results of previous studies [21] , [22] , [26] , PF-06767832, VU6004256 and MIPS1780 have higher affinities at the M 1 mAChR compared to BQCA ( Table 1 ). However, the affinity of BQCA in our study is higher than previously reported values [18] , [27] , [31] , [37] for this compound. This could be due to different experimental conditions including radiolabelled antagonist used, membrane vs. whole cell binding-based assays, incubation time and temperature.…”

Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias

“…Excitingly, the amino acid residues of this extracellular allosteric site of the mAChRs show greater diversity between the different subtypes, thus providing the framework for designing mAChR subtype selective allosteric ligands. In fact, the allosteric sites of the M 1 and M 4 mAChRs have successfully been targeted by rationally designed synthetic allosteric ligands, with (now) a large number of subtype selective allosteric ligands available as pharmacological tools (Ma et al, 2009;Kuduk et al, 2010;Kuduk et al, 2011;Salovich et al, 2012;Le et al, 2013;Mistry et al, 2013;Croy et al, 2014;Huynh et al, 2015;Davoren et al, 2016a;Mistry et al, 2016a;Wood et al, 2016a;Davoren et al, 2016b;Mistry et al, 2016b;Wood et al, 2016b;Wood et al, 2017a;Wood et al, 2017b;Davoren et al, 2017;Long et al, 2017;Tarr et al, 2017;Bertron et al, 2018;Beshore et al, 2018;Dallagnol et al, 2018;Engers et al, 2019a;Engers et al, 2019b;Chopko et al, 2019;Jorg et al, 2019;Poslusney et al, 2019;Schubert et al, 2019;Temple et al, 2019;Temple et al, 2020a;Temple et al, 2020b). Since the orthosteric and allosteric sites are topographically distinct, two ligands can bind one receptor simultaneously.…”

“…Of note, in situations where the orthosteric ligand is a full agonist in both the absence and presence of modulator, the operational model can be simplified to allow for derivation of an overall combined modulatory effect, quantified through the composite parameter, αβ (Aurelio et al, 2009). Application of these allosteric models has been successful in determining structure activity relationships for allosteric modulators of multiple GPCRs including the adenosine A 1 (Ferguson et al, 2008;Aurelio et al, 2009;Aurelio et al, 2010;Aurelio et al, 2011;Valant et al, 2012a) the mAChRs (Mistry et al, 2013;Mistry et al, 2016b;Dallagnol et al, 2018;Jorg et al, 2019;Jorg et al, 2020), the mGlu receptors (Mueller et al, 2012;Gregory et al, 2013;Turlington et al, 2013) and the GLP1-R (Wootten et al, 2012;Wootten et al, 2013b;Hager et al, 2017).…”

“…However, this compound was not progressed into clinical trials due to its poor solubility, limited brain penetration and high plasma protein binding properties (Kuduk et al, 2011). Subsequently, there have been substantial efforts to develop novel M 1 mAChR PAMs with improved physicochemical properties (Mistry et al, 2013;Davie et al, 2014;Kuduk et al, 2014;Davoren et al, 2016a;Mistry et al, 2016a;Davoren et al, 2016b;Mistry et al, 2016b;Panarese et al, 2016;Davoren et al, 2017;Flohr et al, 2017;Bertron et al, 2018;Beshore et al, 2018;Dallagnol et al, 2018;Engers et al, 2019b;Jorg et al, 2019;Mandai et al, 2019;Jorg et al, 2020) High M 4 mAChR-subtype selectivity was first described for the PAM, LY2033298 (Chan et al, 2008). This PAM increased the binding affinity and potency of ACh in CHO cells expressing the human M 4 mAChR, however, LY2033298 was also noted to have some activity at the M 2 mAChR (Chan et al, 2008;Valant et al, 2012b).…”

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

“…Ring opening of aryl B, replacing the tricyclic benzo[ h ]-quinazolin-4(3 H )-one core with quinazolin-4(3 H )-one, gives compound 25 . 104 Compound 25 shows improved “druglike-ness” with lower lipophilicity, topological polar surface area (tPSA), molecular weight and also reduces the toxic DNA-chelation concern for polyaromatic heterocycle scaffolds. The methyl group in the 8-position is critical to maintain affinity for the M 1 mAChR allosteric site compared to 22 with p K B and α β values of 5.15 and 380 for 25 and 5.88 and 370 for 22 , respectively, but lower intrinsic activity (τ B = 1.1) in radioligand binding experiments using FlpIN CHO cells.…”