Methylacridinium and its cholinergic properties.
10-Methylacridinium iodide (methylacridinium; MA) is an inhibitor of cholinesterases. Inhibitors of acetylcholinesterase (AChE) are used in the treatment of myasthenia gravis, Alzheimer's disease, and in the prophylaxis of poisoning with organophosphates. Using spectrophotometric Ellman's method at 436 nm and commercial enzymes we found that MA inhibits AChE by binding with relatively high potency to the peripheral anionic site (IC(50) = 1.68 +/- 0.14 1M; human recombinant AChE) and equally to its inhibition of butyrylcholinesterase (BuChE; IC(50) = 3.54 +/- 0.27 1M; BuChE from human serum). MA also inhibits the binding of [(3)H]N-methylscopolamine to the muscarinic M2 receptor subtype, possibly in an allosteric manner (IC(50) = 1.90 1M). Functional effects on both the enzyme and the receptor could be observed in contractile studies on the isolated rat bladder. The ability of MA to cross the blood-brain barrier (log P = -0.32; polar surface area 3.88) provides prerequisites for a potential use of the drug in the treatment of neural disorders.
Soukup
Ondrej
O
Department of Toxicology, University of Defence, Trebesska 1575, Hradec Kralove 500 01, Czech Republic.
Proska
Jan
J
Binder
Jiri
J
Karasova
Jana Zdarova
JZ
Tobin
Gunnar
G
Jun
Daniel
D
Marek
Jan
J
Musílek
Kamil
K
Fusek
Josef
J
Kuca
Kamil
K
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000494:pharmacology*; D000166:Acridines / Q000737:chemistry; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002091:Butyrylcholinesterase / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000494:pharmacology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D044967:Serum / Q000378:metabolism; D013379:Substrate Specificity; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
D000166:Acridines; D018678:Cholinergic Agents; C028189:N-methylacridine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase