Design and Synthesis of a New Series of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure-Activity Relationship

Autor:	Regina Miller, Michele Matchett, Nicholas J. Lodge, Yulia Benitex, Thaddeus F. Molski, Wendy Clarke, John E. Macor, Rulin Zhao, Robert Zaczek, Linda J. Bristow, Amy Easton, Christiana I. Iwuagwu, JoAnne E Natale, Haiquan Fang, Ronald J. Knox, Baoqing Ma, F. Christopher Zusi, Siva Digavalli, James H. Cook, Matthew D. Hill, Francine L. Healy, Debra J. Post-Munson, Jingfang Qian Cutrone, Daniel G. Morgan, Bei Wang, Richard E. Olson, Qi Gao, Rex Denton, Robert A. Mate, Ivar M. McDonald, Dalton King, Meredith Ferrante, Kimberley A. Lentz, Kelli M. Jones, Judith A. Siuciak, Lizbeth Gallagher
Rok vydání:	2016
Předmět:	0301 basic medicine alpha7 Nicotinic Acetylcholine Receptor Stereochemistry Substituent Partial agonist 03 medical and health sciences chemistry.chemical_compound Cyclooctanes Mice Structure-Activity Relationship 0302 clinical medicine Drug Discovery Structure–activity relationship Animals Humans Spiro Compounds Nicotinic Agonists Receptor Maze Learning Oxazole Bicyclic molecule Dose-Response Relationship Drug Molecular Structure Combinatorial chemistry 030104 developmental biology chemistry Drug Design Molecular Medicine Pharmacophore Selectivity 030217 neurology & neurosurgery
Zdroj:	Journal of medicinal chemistry. 59(24)
ISSN:	1520-4804
Popis:	The design and synthesis of a series of quinuclidine-containing spirooxazolidines (“spiroimidates”) and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4′H-4-azaspiro[bicyclo[2.2.2]octane-2,5′oxazol]-2′-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a7168f463fa8dafe0bc3dd8512c11678 https://pubmed.ncbi.nlm.nih.gov/27958732 Zobrazit plný text záznamu