Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR

• Published in: Journal of lipid mediators and cell signalling Vol. 13; no. 3; pp. 207 - 222
• Main Authors: Texier, Laurence Le, Favre, Edith, Ronzani, Nello, Massicot, France, Blavet, Nadine, Pirotzky, Edouardo, Godfroid, Jean-Jacques
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.1996
• Subjects: Acetylcholinesterase - biosynthesis; Acetylcholinesterase - pharmacology; Acytetylcholinesterase inhibitor; Adult; Alzheimer's disease; Animals; Cholinesterase Inhibitors - pharmacology; Furans - pharmacology; Humans; Male; Mice; Mice, Inbred C57BL; PAF antagonist; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - chemistry; Structure-Activity Relationship; Tetrahydrofuran; Tetrahydrofuran; Acytetylcholinesterase inhibitor; PAF antagonist; Alzheimer's disease; Structure-activity relationship
• ISSN: 0929-7855
• DOI: 10.1016/0929-7855(95)00053-4

2,5-disubstituted tetrahydrofuran derivatives display a dual functionality: they are PAF antagonists and acetylcholinesterase (AChE) inhibitors. In vitro anti-AChE activity and in vivo trials are presented herein. These compounds are competitive and potent AChE inhibitors. Structure-activity relationships are described and compared with PAF-antagonist results. The presence of an onium group, a suitable distance supplied by a chain of 7 or 10 carbon atoms separating the function from the polar head and an appreciable chain hydrophobicity (4 < Σf < 7) are the main required for a dual activity. The derivatives are evaluated in a mouse passive avoidance model. Only compounds with both activities are able to reverse scopolamine-induced amnesia. In addition, they display a very weak toxicity.