title: Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
abstract: The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States. Electronic address: bfliu@lilly.com.
authors: Bin
authors: B
authors: Liu
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Carrie H
authors: CH
authors: Croy
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Stephen A
authors: SA
authors: Hitchcock
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Jennifer R
authors: JR
authors: Allen
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Zhigang
authors: Z
authors: Rao
authors: Eli Lilly and Company, Windlesham, Surrey, UK.
authors: David
authors: D
authors: Evans
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Mark G
authors: MG
authors: Bures
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: David L
authors: DL
authors: McKinzie
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Marla Leigh
authors: ML
authors: Watt
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: G
authors: G
authors: Stuart Gregory
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Marvin M
authors: MM
authors: Hansen
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Paul J
authors: PJ
authors: Hoogestraat
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: James A
authors: JA
authors: Jamison
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Fese M
authors: FM
authors: Okha-Mokube
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Robert E
authors: RE
authors: Stratford
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: William
authors: W
authors: Turner
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States.
authors: Frank
authors: F
authors: Bymaster
authors: Lilly Research Laboratories, Indianapolis, IN 46285, United States. Electronic address: felder_christan_c@lilly.com.
authors: Christian C
authors: CC
authors: Felder
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D043643:Receptor, Muscarinic M1
keywords: Alzheimer’s disease; Drug discovery; Multi-topic ligand; Muscarinic receptor; Structure–activity-relationship