title: The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test.
abstract: OBJECTIVE
  The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil.
  
  
  METHODS
  Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method.
  
  
  RESULTS
  QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points.
  
  
  CONCLUSIONS
  The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Misik
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Nepovimova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Cabelova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kassa
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000633:toxicity; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000633:toxicity*; D017208:Rats, Wistar; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D010880:Piperidines; D013619:Tacrine; D011813:Quinuclidinyl Benzilate; D000077265:Donepezil
keywords: Alzheimer disease; acetylcholine; acetylcholinesterase; donepezil; spatial orientation; tacrine