Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M1 agonists. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Liu, Bin; Croy, Carrie H.; Hitchcock, Stephen A.; Allen, Jennifer R.; Rao, Zhigang; Evans, David; Bures, Mark G.; McKinzie, David L.; Watt, Marla Leigh; Stuart Gregory, G.; Hansen, Marvin M.; Hoogestraat, Paul J.; Jamison, James A.; Okha-Mokube, Fese M.; Stratford, Robert E.; Turner, William; Bymaster, Frank; Felder, Christian C.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4158
• Page End: 4163
• Publication Date: 2015-10-01
• Subjects: KOQVBYSCBCRVQJ-SVUXJTORSA-N; GPCR G protein-coupled receptors -- CHO Chinese hamster ovary -- GTPγ35S [35S]-guanosine-5′-O-(3-thio)triphosphate -- BOC butoxycarbony -- EC50 half maximal effective concentration of drug -- pKa log of acid dissociation constant (Ka) -- Log D log of the partition coefficient of molecule -- AUC area under the curve -- SAR structure–activity relationship -- VDW van der Waals; Drug discovery -- Multi-topic ligand -- Muscarinic receptor -- Alzheimer's disease -- Structure–activity-relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.011
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.