Novel anti-Alzheimer´s therapeutics

Cholinesterase inhibitors

Cholinesterase inhibitors are currently used for Alzheimer’s disease therapy, in the treatment of Myasthenia gravis and as antidotes against organophosphorus poisoning (e.g. sarin, soman, tabun). The aim of our group is to design, synthesize and biologically evaluate novel cholinesterase inhibitors that could be used as aforementioned.

Working group performs:

in silico design of novel drugs
design of small molecules targeting cholinesterases (acetylcholinesterase, butyrylcholinesterase)
targeted synthesis of small centrally active molecules inhibiting cholinestearses and other targets e.g.NMDA receptores, GSK-3beta, targets with the activity against oxidative stress
international cooperation with other labs focused on cholinesterase research

Team:

assoc. prof. Jan Korabecny, PhD.

assoc. prof. Rafael Dolezal, PhD.

prof. PharmDr. Ondrej Soukup, PhD.

RNDr. Eva Mezeiova, PhD.

Barbora Svobodova, PhD.

Modulators of receptors

The main concern of this working group is to study the interaction of new substances, with especially cholinergic receptors (muscarinic and nicotinic), which are important in the treatment of both Alzheimer's disease and organophosphorus poisoning. Currently, the working group focuses on design, preparation and in - vitro testing of potential agonists of M1 muscarinic receptor and antagonists of the central and peripheral nicotinic receptors. Recently, attention has also been paid to the chemical synthesis of potential antagonist of NMDA receptors (derivatives of memantine), which are also interesting in terms of the Alzheimer's disease therapy.

Team:

prof. PharmDr. Ondrej Soukup, PhD.

assoc. prof. Jan Korabecny, PhD.

ABAD (Aβ-binding alcohol dehydrogenase)

Our aim is design, synthesis and identification of small molecules affecting mitochondrial enzymes, especially ABAD (Aβ-binding alcohol dehydrogenase), and the interaction of mitochondrial enzymes with Aβ.

Working group performs:

in silico molecular modelling
design of small molecules targeted to mitochondrial enzymes (ABAD)
targeted synthesis of small molecules modulating the activity of mitochondrial enzymes (ABAD)
structure-activity relationship of synthesized modulators of mitochondrial enzymes (ABAD)

Team:

prof. PharmDr. Kamil Musilek, Ph.D.

PharmDr. Ondrej Benek, PhD.

Barbora Svobodova, PhD.

Neuroprotectants

The main aim of this working group is to develop novel neuroprotectants or pro-cognitive agents that can be used in the treatment of Alzheimer's disease as well as at other diseases associated with neurodegeneration. The mechanism of action of these agents is primarily focused on the selective inhibition of NMDA receptors, which protects against excitotoxicicity caused by glutamate. The added value of the novel compounds is the inhibition of acetylcholinesterase, which provides additive pro-cognitive efficacy. Furthermore, the group focuses on reducing the inflammatory processes in the brain and cellular models of neuroinflammation.

Main tasks:

rational in silico design of new small molecules targeting AChE and NMDA receptors

targeted synthesis of small organic molecules targeting AChE and NMDA receptors
Evaluation of the structure-activity relationship of the prepared modulators; NMDA testing in cooperation with the Institute of Experimental Medicine of the Academy of Sciences of the Czech Republic (Dr. Martin Horák)

in vivo study of candidates in cooperation with the National Institute of Mental Health (Dr. Karel Valeš)

Team:

prof. PharmDr. Ondrej Soukup, PhD.

assoc. prof. Jan Korabecny, PhD.

RNDr. Eva Mezeiova, PhD.

Tereza Kobrlova, PhD.

PharmDr. Lukas Prchal, PhD.

assoc. prof. Rafael Dolezal, PhD.

Martin Novak, PhD.

Marketa Benková, PhD.

RNDr. Lenka Pulkrabkova