Identification of Multiple 5‑HT4 Partial Agonist Clinical Candidates for the Treatment of Alzheimer’s Disease

• Published in: Journal of medicinal chemistry Vol. 55; no. 21; pp. 9240 - 9254
• Main Authors: Brodney, Michael A, Johnson, David E, Sawant-Basak, Aarti, Coffman, Karen J, Drummond, Elena M, Hudson, Emily L, Fisher, Katherine E, Noguchi, Hirohide, Waizumi, Nobuaki, McDowell, Laura L, Papanikolaou, Alexandros, Pettersen, Betty A, Schmidt, Anne W, Tseng, Elaine, Stutzman-Engwall, Kim, Rubitski, David M, Vanase-Frawley, Michelle A, Grimwood, Sarah
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.11.2012; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - psychology; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Chemistry, Medicinal; CHO Cells; Cognition Disorders - drug therapy; Cricetinae; Cricetulus; Cyclic AMP - biosynthesis; Dogs; Drug Partial Agonism; Haplorhini; HEK293 Cells; Humans; In Vitro Techniques; Indoles - chemical synthesis; Indoles - pharmacokinetics; Indoles - pharmacology; Life Sciences & Biomedicine; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver - metabolism; Permeability; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - pharmacokinetics; Piperidines - pharmacology; Protein Isoforms - metabolism; Pyrans - chemical synthesis; Pyrans - pharmacokinetics; Pyrans - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4 - metabolism; Science & Technology; Serotonin 5-HT4 Receptor Agonists - chemical synthesis; Serotonin 5-HT4 Receptor Agonists - pharmacokinetics; Serotonin 5-HT4 Receptor Agonists - pharmacology; Stereoisomerism; Structure-Activity Relationship; CHOLINERGIC HYPOTHESIS; LIGANDS; MEMORY; ACETYLCHOLINE; RECEPTOR AGONISTS; PRUCALOPRIDE; DRUGS; BINDING

The cognitive impairments observed in Alzheimer’s disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT4) agonists are reported to modulate cholinergic function and therefore may provide a...