TARGETING TACRINE HEPATOTOXICITY ASSOCIATED WITH THE CYP BIOTRANSFORMATIONMeeting abstracts
- 1 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Králové, The Czech Republic
- 2 Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, The Czech Republic
- 3 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, The Czech Republic
- 4 National Institute of Mental Health, Topolova 748, 250 67 Klecany, The Czech Republic
Current symptomatic pharmacotherapy for Alzheimer’s disease is primarily focused on acetylcholinesterase inhibitors and blocking of the NMDA receptor (N-methyl-D-aspartate). Tacrine, a molecule with both of the mechanisms of action, was withdrawn from the market in 2013 after 20 years of use due to the hepatotoxicity probably caused by its 7-hydroxytacrine metabolite. A rationale substitution of the tacrine molecule can potentially hinder the formation of a toxic species. The introduction of the methoxy or phenoxy group to position 7 led to 7-phenoxytacrine (7-PhO-THA) which we hypothesize to bypass the toxic metabolization via 7-OH tacrine and quinon methid. Furthermore, 7-PhO-THA was confirmed being of dual potency, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed that 7-PhO-THA manages to avoid side effects, symptoms of schizophrenia typical for NMDA antagonists.
Keywords: tacrine; hepatotoxicity; CYP450; biotransformation; quinon methid
Published: June 20, 2022 Show citation