Differential inhibition of rat brain acetylcholinesterase molecular forms by 7-methoxytacrine in vitro.
The effects of 7-methoxytacrine (7-MEOTA), a less toxic derivative of tetrahydroaminoacridine, on the activity of acetylcholinesterase (AChE) molecular forms were investigated in vitro. AChE molecular forms were separated by sucrose gradient sedimentation from homogenates of the frontal cerebral cortex prepared with buffer containing Triton X-100 (soluble + membrane-bound enzyme). Two molecular forms, namely 10S and 4S corresponding to globular tetrameric (G4) and monomeric (G1) forms, respectively, were detected; their molecular weights were 220,000 and 54,000 Da. A significantly higher sensitivity to 7-MEOTA of G4 than of G1 forms was observed. The Ki values were 0.21 +/- 0.07 microM for the former and 0.70 +/- 0.15 microM for the latter. The differential inhibition of AChE molecular forms by 7-MEOTA is discussed in relation to its possible clinical application for treatment of disorders such as Alzheimer's disease, in which a reduction of brain cholinergic neurotransmission is believed to play a role.
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000302:isolation & purification; D000544:Alzheimer Disease / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D013619:Tacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity
D000806:Angiotensin-Converting Enzyme Inhibitors; D013619:Tacrine; C016222:7-methoxytacrine; D000110:Acetylcholinesterase