Pharmacological Characterization of LY593093, an M1 Muscarinic Acetylcholine Receptor-Selective Partial Orthosteric Agonist

Abstract

Alzheimer's disease and schizophrenia are characterized by expression of psychotic, affective, and cognitive symptoms. Currently, there is a lack of adequate treatment for the cognitive symptoms associated with these diseases. Cholinergic signaling and, in particular, M1 muscarinic acetylcholine receptor (m1AChR) signaling have been implicated in the regulation of multiple cognitive domains. Thus, the M1AChR has been identified as a therapeutic drug target for diseases, such as schizophrenia and Alzheimer's disease, that exhibit marked cognitive dysfunction as part of their clinical manifestation. Unfortunately, the development of selective M1 agonist medications has not been successful, mostly because of the highly conserved orthosteric acetylcholine binding site among the five muscarinic receptor subtypes. More recent efforts have focused on the development of allosteric M1AChR modulators that target regions of the receptor distinct from the orthosteric site that are less conserved between family members. However, orthosteric and allosteric ligands may differentially modulate receptor function and ultimately downstream signaling pathways. Thus, the need for highly selective M1AChR orthosteric agonists still exists, not only as a potential therapeutic but also as a pharmacological tool to better understand the physiologic consequences of M1AChR orthosteric activation. Here, we describe the novel, potent and selective M1AChR orthosteric partial agonist. This compound demonstrates modest to no activity at the other muscarinic receptor subtypes, stimulates G␣ qcoupled signaling events as well as ␤-arrestin recruitment, and displays significant efficacy in in vivo models of cognition.

Equilibrium Assays Are Required to Accurately Characterize the Activity Profiles of Drugs Modulating Gq-Protein-Coupled Receptors

“…Characterization of Agonist Effect for Full and Partial Agonists. The effects of the muscarinic full agonist ACh and partial agonist alvameline (Watt et al, 2011) were measured in functional assays utilizing CHO cells expressing muscarinic M1 receptors. As seen in Fig.…”

Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

“…6,17–20 Recently, numerous additional M 1 full and partial agonists have been reported with improved properties and efficacy in cognition models. 21–23 Positive allosteric modulators (PAMs) from three structural classes, 5 – 7 , have also been reported, with exquisite selectivity for M 1 versus M 2 –M 5 and BARs, allowing limited in vivo proof of concept studies to be conducted. 24–26,28,29,31,32 For all of these PAMs, both DMPK properties and CNS penetration are barely adequate for in vivo studies; 24–26,28,29,31,32 however, two scaffolds variants of the BQCA PAM scaffold have overcome the DMPK issues and afforded PAMs with good properties and CNS exposure.…”

M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluAl subunit

“…Consistent with these findings, knockout mutation or pharmacologic manipulation of M1 mAChRs impairs learning and memory (8,12). Activation or positive allosteric modulation of M1 mAChRs improves cognitive performance and ameliorates memory deficits in animal models (13)(14)(15). More importantly, M1 mAChR activation has been reported to improve memory in humans (16).…”