Nicotinic acetylcholine receptors are ligand-gated ion channels which are located on neuromuscular junction and in central and perifric nervous system. Activity of nicotinic receptor might be modulated by variety of pharmacological agents. In this work, we have focused on the study of the inhibition effect of tacrine and its derivatives on the nicotinic acetycholine receptors of muscle and neuronal type. These derivatives function as acetylcholinesterase inhibitors and also interact with nicotinic acetylcholine receptors. The majority of current forms of treatment of Alzheimer's disease is based on cholinesterase inhibitors. We have studied the mechanism of tacrine and its derivatives by using patch clamp method in the configuration of whole-cell recording. Powered by TCPDF (www.tcpdf.org)

This thesis deals with effects of some chosen 7-methoxitacrine (7-MEOTA) analogues on enzymatic activity of acetylcholinesterase (AChE). 7-MEOTA is a derivative of tacrine, which had been used for symptomatic treatment of Alzheimer's disease (AD), until drugs with better therapeutic index were developed. 7-MEOTA the same way as tacrine therapeutically acts by inhibition of acetylcholinesterase and a neurotransmitter acetylcholine rise in the organism. It shows similar strength and type of inhibition, but it's less toxic contrary to tacrine. Some of the previously examined analogues of 7-MEOTA were as strong or even stronger AChE inhibitors than 7-MEOTA and so promising future medicaments. However, all the compounds analyzed in this thesis showed weaker enzymatic reaction inhibition and AChE affinity. For each of the examined compounds IC50, Ki and Ki' were calculated and AChE inhibition type was determined. All the 7-MEOTA analogues showed a mixed type of the inhibition. The theoretical part of this thesis deals with manifestations and origins of AD, its genetic factors etc. and tries to show some of the anthropological findings a theories connected with the theme.

This thesis deals with effects of some chosen 7-methoxitacrine (7 MEOTA) analogues on enzymatic activity of acetylcholinesterase (AChE). 7-MEOTA is a derivative of tacrine, which had been used for symptomatic treatment of Alzheimer's disease (AD), until drugs with better therapeutic index were developed. 7-MEOTA the same way as tacrine therapeutically acts by inhibition of acetylcholinesterase and a neurotransmitter acetylcholine rise in the organism. It shows similar strength and type of inhibition, but it's less toxic contrary to tacrine. Some of the previously examined analogues of 7-MEOTA were as strong or even stronger AChE inhibitors than 7-MEOTA and so promising future medicaments. However, all the compounds analyzed in this thesis showed weaker enzymatic reaction inhibition and AChE affinity. For each of the examined compounds IC50, Ki and Ki' were calculated and AChE inhibition type was determined. All the 7 MEOTA analogues showed a mixed type of the inhibition. The theoretical part of this thesis deals with manifestations and origins of AD, its genetic factors etc. and tries to show some of the anthropological findings a theories connected with the theme. Powered by TCPDF (www.tcpdf.org)

In preclinical research on Alzheimer's disease pharmacotherapy, attention is paid to multipotent compounds, enabling intensification of the effect by targeting multiple pathophysiological mechanisms. The aim of the thesis was to assess the effect of multipotent compounds and combination therapy in models of cognitive deficit in the rat. The mechanism of action of the tested compounds was modulation of neurotransmitter systems. The aim of the first part of the study was to compare the effect of experimental monotherapy and combination therapy with an N-methyl-D-aspartate (NMDA) receptor antagonist and a γ-aminobutyric acid type A (GABAA) receptor positive modulator in the trimethyltin-induced model. Superiority of the combination therapy was proven by histological analysis of hippocampal neurodegeneration; however, it did not reach statistical significance in the cognitive test. The other part of the thesis focused on multipotent tacrine derivatives. We demonstrated a positive effect of 6- chlorotacrine-6-nitrobenzothiazole hybrid, as well as 6-chlorotacrine-L-tryptophan hybrid, acting as acetylcholinesterase inhibitors, in the scopolamine-induced model of cognitive deficit. Besides, we demonstrated a low risk of serious side effects of other tacrine derivatives acting as NMDA receptor antagonists....