Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR.
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 < sigma f < 7) are the main features 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.
Le Texier
L
L
Université Paris 7-Denis Diderot, France.
Favre
E
E
Ronzani
N
N
Massicot
F
F
Blavet
N
N
Pirotzky
E
E
Godfroid
J J
JJ
D000110:Acetylcholinesterase / Q000096:biosynthesis* / Q000494:pharmacology; D000328:Adult; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D005663:Furans; D010972:Platelet Activating Factor; C018674:tetrahydrofuran; D000110:Acetylcholinesterase