In vivo investigations on the cholinesterase-inhibiting effects of tricyclic quinazolinimines: scopolamine-induced cognitive impairments in rats are attenuated at low dosage and reinforced at higher dosage.
Tricyclic quinazolinimines as a novel class of potent inhibitors of cholinesterases in vitro are micro- and sub-micromolar inhibitors with activities at both acetyl- (AChE) and butyrylcholinesterase (BChE) or at BChE only. To further establish the antiamnesic properties of this class of compounds, an in vivo test system has been established. Cognitive impairment in rats was reversibly induced by scopolamine (0.05 mg/100 g body weight) and evaluated in an eight-arm radial maze. A representative quinazolinimine (MD212) showed attenuation of cognitive deficits at a low dosage (0.01 mg/100 g body weight), whereas at a high dosage (>0.1 mg/100 g body weight) the effect of scopolamine is markedly reinforced. As MD212 applied alone does not influence rat's cognition at all, the reinforcement of scopolamine effect has to be due to the amplification of scopolamine action possibly by (1) inhibition of scopolamine metabolism, (2) influence of scopolamine on MD212 metabolism or (3) allosteric modulation of mACh receptors. Receptor-binding studies proved hypothesis (3): MD212 stabilizes [3H]N-methylscopolamine binding to muscarinic receptors allosterically.
Appenroth
D
D
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Jena, Germany.
Decker
M
M
Tränkle
C
C
Mohr
K
K
Lehmann
J
J
Fleck
C
C
D000494:Allosteric Regulation; D000818:Animals; D001392:Azocines / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007097:Imines / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000494:pharmacology*; D014316:Tritium
D001392:Azocines; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D007097:Imines; C529219:N-benzyl-N-(6,7,8,9,10,11-hexahydro-13H-azocino(2,1-b)quinazolin-13-ylidene)amine; D011799:Quinazolines; D014316:Tritium; D012601:Scopolamine
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