PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems

Abstract

Positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M PAMs may reduce efficacy and contribute to adverse effect liability. However, the M PAM PF-06827443 was reported to have only weak agonist activity at human M receptors but produced M-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.

Biased M1positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

“…Previously, we found that the presence of allosteric agonist activity in M1 PAMs can limit in vivo efficacy and increase adverse effect liability (13,14,19,20). Thus, minimalizing agonist activity can maximize the therapeutic window of M1 PAMs (13,(19)(20)(21). These previous studies demonstrate that a complete understanding of the different pharmacological properties of structurally distinct M1 PAMs is essential to fully evaluate clinical candidates and maximize their therapeutic potential.…”

“…While these preclinical findings are extremely promising for the potential of M1 PAMs to reverse cognitive deficits in patients, M1 PAMs can display a diverse range of pharmacological properties, some of which are potentially detrimental to in vivo efficacy. Previously, we found that the presence of allosteric agonist activity in M1 PAMs can limit in vivo efficacy and increase adverse effect liability (13,14,19,20). Thus, minimalizing agonist activity can maximize the therapeutic window of M1 PAMs (13,(19)(20)(21).…”

VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events

“…The first amide moiety surveyed was the (3S,4R)-3hydroxy-4 amino tetrahydropyranyl (THP) amide, well documented to engender potent M 1 PAMs, but with undesired potent M 1 agonist activity. 11,[13][14][15][16][17]19 As we previously reported, M 1 PAM potencies below 100 nM, coupled with M 1 agonist activity, generally lead to robust cholinergic AEs. 19 As anticipated, analogs 14 ( Table 1) with diverse southern heterobiaryl tails provided potent M 1 ago-PAMs.…”

“…As the analogous cyclohexyl congener 15 of THP 14 generally afforded a lower degree of M 1 agonism, we next evaluated such analogs. As shown in Table 2, analogs 15 were also potent M 1 ago-PAMs (15a−c), but with reduced M 1 agonism relative to 14, 11,[13][14][15][16][17]19 as well as a moderately potent M 1 PAM (15d). Interestingly, both 15b and 15c were not CNS penetrant in rat, with K p values below level of quantitation (BLQ), despite favorable CNS MPO scores (4−5).…”

T‐495, a novel low cooperative M1 receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk

“…Therefore, cooperativity, but not agonist activity, of M 1 R PAMs may contribute to the improved and superior pharmacological profile. However, to more precisely quantify agonist activity, physiological receptors in brain slices and primary cells, rather than cell lines, should be used, because agonist activity is greatly affected by various factors including the degree of receptor reserve . Unfortunately, only low‐throughout electrophysiological assays using brain slices are available for characterization of the agonist activity of M 1 R PAMs.…”