TY - JOUR T1 - Pharmacological Characterization of LY593093, an M1 Muscarinic Acetylcholine Receptor-selective Partial Orthosteric Agonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.182063 SP - jpet.111.182063 AU - Marla L. Watt AU - Douglas A. Schober AU - Steven Hitchcock AU - Bin Lui AU - Amy K. Chesterfield AU - David McKinzie AU - Christian C. Felder Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/05/10/jpet.111.182063.abstract N2 - 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 M1 muscarinic acetylcholine receptor (m1AChR) signaling in particular, 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 that exhibit marked cognitive dysfunction as part of their clinical manifestation. Unfortunately, the development of selective M1 agonist medications has not been successful, mostly due to 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 LY593093 (N-[(1R,2R)-6-({(1E)-1-[(4-fluorobenzyl)(methyl)amino]ethylidene})amino)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]biphenyl-4-carboxamide). This compound demonstrates modest to no activity at the other muscarinic receptor subtypes, stimulates Gαq-coupled signaling events as well as β-arrestin recruitment and displays significant efficacy in in vivo models of cognition. ER -