Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M₁ Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles

Abstract

Targeting allosteric sites at M muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.

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

“…Next, intermediates 12 a – d were obtained from a Suzuki coupling reaction with (2‐hydroxyphenyl)boronic acid in yields ranging from 14–83 %. Lead 1 and novel analogues 13 b – d were obtained by alkylation with the previously synthesized 4‐(4‐(chloromethyl)phenyl)‐1‐methyl‐1 H ‐pyrazole [13] in moderate to good yields (15–72 %). Lastly, alcohol 1 was O‐alkylated with methyl iodide, using sodium hydride as the base to afford compound 14 in 25 % yield.…”

“…Compound 24 d was resistant to demethylation of both methoxy groups by these methods, but ultimately treatment of 25 c with p ‐toluenesulfonic acid and lithium chloride in NMP at 180 °C, yielded 25 d in a moderate 34 % yield. Finally, intermediates 25 a – d were alkylated with 4‐(4‐(chloromethyl)phenyl)‐1‐methyl‐1 H ‐pyrazole [13] using either silver carbonate or potassium carbonate as the base to obtain analogues 26 a and 26 b – d , respectively.…”

“…Functional activity of the synthesized analogues as racemic mixtures was investigated in IP 1 accumulation assays at the M 1 mAChR, as described previously [13–14] . ACh concentration‐response curves were generated in the absence or presence of a 1 and 10 μM concentration of each modulator.…”

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.…”

Current Advances in Allosteric Modulation of Muscarinic Receptors

“…Namely, two new classes of M 1 -selective PAMs have been developed. Derivatives of heterocyclic carboxamides display various degrees of intrinsic activity and various modulatory profiles of affinity and efficacy of acetylcholine [77]. Similarly, derivatives of 4-phenylpyridin-2-one ( Figure 8) display a diverse range of activities, ranging from pure PAMs to pure allosteric agonists [78].…”