BACKGROUND: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. METHODS: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. RESULTS: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. CONCLUSION: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.

• MeSH
• alkylace MeSH
• amyloidní beta-protein účinky léků   MeSH
• cholesterol metabolismus   MeSH
• cholin metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• fluidita membrány účinky léků   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kvartérní amoniové sloučeniny chemie   farmakologie   MeSH
• membránové mikrodomény účinky léků   MeSH
• mozková kůra účinky léků   MeSH
• potkani Wistar MeSH
• proteiny přenášející kationty účinky léků   MeSH
• stereoizomerie MeSH
• synaptozomy účinky léků   metabolismus   MeSH
• takrin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-methoxytacrine MeSH Prohlížeč
• amyloidní beta-protein MeSH
• cholesterol MeSH
• cholin MeSH
• cholinesterasové inhibitory MeSH
• CHT1 protein, rat MeSH Prohlížeč
• kvartérní amoniové sloučeniny MeSH
• proteiny přenášející kationty MeSH
• takrin MeSH