Probing Structural Requirements of Positive Allosteric Modulators of the M₄ Muscarinic Receptor

Abstract

The M4 mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M4 PAMs derived from VU0152100 and VU10005. These compounds investigate the pharmacological effects of previously identified methoxy and fluoro substituents, providing useful estimates of affinity (KB), cooperativity (αβ), and direct agonist properties (τB).

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

“…An advantage of the operational model as applied to SAR is that it can almost always be fitted to experimentally derived data to provide estimates of some, or all, of its parameters with regards both to allosteric modulators (Aurelio et al, 2009;Gregory et al, 2012;Valant et al, 2012a;Huynh et al, 2013;Mistry et al, 2013) and biased agonists (Tschammer et al, 2011b;Shonberg et al, 2013;Szabo et al, 2014). Table 1 illustrates an example of allosteric modulator SAR determined through analysis of the effects of various thienopyridine modulators on acetylcholine-mediated ERK1/2 phosphorylation at the M 4 mAChR.…”

“…The first, EC 50 , is an empirical potency derived from a simple titration of test compound against a fixed concentration (and hence, effect) of orthosteric agonist. The other three parameters, K B , ab, and t B , are derived from operational model analysis of the entire acetylcholine concentration-response relationship in the presence of increasing modulator concentrations (Huynh et al, 2013).…”

“…Thus, it is the latter parameter that can be chemically dialed up or down in this series, not the former. Determination of operational efficacies (t B ) also allows one to look for correlations between the ability of the modulator to activate the receptor and its ability to modulate the orthosteric agonist (ab), which appears to be the case in this instance (Huynh et al, 2013).…”

Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M2and M4Receptors

“…After the 2004 patent filing by Eli Lilly (Rubio and Hillard, 2006), studies on molecules such as LY2033298 (Chan et al, 2008;Nawaratne et al, 2008Nawaratne et al, , 2010Leach et al, 2010Leach et al, , 2011Suratman et al, 2011;Gannon and Millan, 2012;Valant et al, 2012) and others, e.g., VU10010 Shirey et al, 2008;Bridges et al, 2010 [http://www.ncbi.nlm.nih.gov/books/NBK143196/]; Lewis et al, 2010;Dencker et al, 2012;Salovich et al, 2012;Huynh et al, 2013;Le et al, 2013), explored the structureactivity relationship around this scaffold and the in vivo efficacy of such molecules in animal models. Concomitant structure-function work using methods such as site-directed mutagenesis have allowed the mapping of the various ligand binding sites to the M 4 receptor and, in one instance, the M 2 receptor, and revealed critical regions involved in the receptor activation mechanism (Nawaratne et al, 2008(Nawaratne et al, , 2010Leach et al, 2011;Suratman et al, 2011;Valant et al, 2012).…”

Challenges in the development of an M 4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs

“…M 4 (muscarinic acetylcholine receptor subtype 4) positive allosteric modulators (PAMs) represent an exciting therapeutic strategy to treat multiple domains of schizophrenia, 1-18 as well as other CNS disorders, 19,20 via a new molecular mechanism. 21 However, the great potenital has been hampered by limited chemical diversity centered on a 3-amino-thieno[2,3- b ]pyridine core, as in 1 - 4 , (Figure 1), which engenders steep SAR, species differences (rat versus human M 4 PAM potency, affinity/cooperativity and subtype selectivity), poor solubility, and/or low CNS penetration.…”