Development of Novel 4‐Arylpyridin‐2‐one and 6‐Arylpyrimidin‐4‐one Positive Allosteric Modulators of the M₁ Muscarinic Acetylcholine Receptor

Abstract

This study investigated the structure‐activity relationships of 4‐phenylpyridin‐2‐one and 6‐phenylpyrimidin‐4‐one M1 muscarinic acetylcholine receptor (M1 mAChRs) positive allosteric modulators (PAMs). The presented series focuses on modifications to the core and top motif of the reported leads, MIPS1650 (1) and MIPS1780 (2). Profiling of our novel analogues showed that these modifications result in more nuanced effects on the allosteric properties compared to our previous compounds with alterations to the biaryl pendant. Further pharmacological characterisation of the selected compounds in radioligand binding, IP1 accumulation and β‐arrestin 2 recruitment assays demonstrated that, despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM 7 f is a potential lead candidate for further development of peripherally restricted M1 PAMs, due to its lower blood–brain‐barrier (BBB) permeability and improved exposure in the periphery compared to lead 2.

Targeting the M1 muscarinic acetylcholine receptor in Alzheimer’s disease

“…On the other hand, PAM-agonists, in addition to enhancing the pharmacological activity of the bound orthosteric ligand, exert their own direct intrinsic agonist effects on the receptor, independent of the bound orthosteric ligand [ 116 , 119 ]. Negative allosteric modulators (NAMs) bind to the allosteric site of the receptor to reduce the pharmacological binding and/or potency of the bound orthosteric ligand.…”

Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias

“…For signaling assays, the ATCM has been incorporated into an operational model that also allows for quantification of allosteric effects on orthosteric agonist efficacy (β) as well as direct orthosteric (τ A ) and allosteric (τ B ) agonism (Price et al, 2005;Leach et al, 2007). In operational terms, β values of >1 denote positive efficacy modulation, values of β < 1 but > 0 denote 2016), and Jorg et al (2020). Data were fit with the simplified operational model of allostery and agonism (Aurelio et al, 2009), to quantify the cooperativity (αβ) and intrinsic efficacy (τ B ) parameters.…”

“…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).…”

“…(D) The NAL, compound 13b, has no effect on the potency of ACh toward IP 1 accumulation at the M 1 mAChR. Data are from van der Westhuizen et al (2018), Berrizzi et al (2016), andJorg et al (2020). Data were fit with the simplified operational model of allostery and agonism(Aurelio et al, 2009), to quantify the cooperativity (αβ) and intrinsic efficacy (τ B ) parameters.…”