11 research outputs found
Concentration of donepezil in the cerebrospinal fluid of AD patients: Evaluation of dosage sufficiency in standard treatment strategy
Time-Course Changes of Acetylcholinesterase Activity in Blood and Some Tissues in Rats After Intoxication by Russian VX
Tacrine and its 7-methoxy derivate; time-change concentration in plasma and brain tissue and basic toxicological profile in rats
A comparison of reactivating and therapeutic efficacy of the oxime K203 and its fluorinated analog (KR-22836) with currently available oximes (obidoxime, trimedoxime, HI-6) against tabun in rats and mice
A comparison of tabun-inhibited rat brain acetylcholinesterase reactivation by three oximes (HI-6, obidoxime, and K048) in vivo
Novel D<SUB>2</SUB>/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment
Changes of rat plasma total low molecular weight antioxidant level after tabun exposure and consequent treatment by acetylcholinesterase reactivators
Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit A\u3b242 self-aggregation (58.6 \ub1 5.1% at 50 \u3bcM) as well as hAChE-induced A\u3b240 aggregation (48.3 \ub1 6.3% at 100 \u3bcM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia