PhD Open Position 2024/2025

Development of novel pharmacological compounds acting on NMDA receptors

Supervisor:

Head of the Department
Martin Horák, Ph.D.

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Project description

N-methyl-D-aspartate (NMDA) receptors are a family of ionotropic glutamate receptors that play a crucial role in excitatory neurotransmission in the mammalian central nervous system. However, their dysfunction leads to many neuropathological disorders, including neurodegenerative diseases and cognitive deficits. Collaborating with the Biomedical Research Centre in Hradec Kralove, we will develop a series of compounds based on tacrine and MK-801 that modulate NMDA receptor activity using unique mechanisms.

In this Ph.D. project, you will employ sophisticated molecular biological and electrophysiological approaches, including whole-cell and single-channel measurements on transfected HEK293 cells, as well as synaptic measurements on hippocampal slices from two mouse models of Alzheimer’s disease, and two knock-in mouse models carrying pathogenic variants in GRIN genes. Finally, you will test the effect of the selected drugs using EEG, basic behavioural tests, and in vivo microscopy. Our goal is to optimise the physicochemical properties of the novel compounds, including their solubility, blood-brain barrier permeability, affinity, and rate of action on individual NMDA receptor subtypes, but to minimise their side effects in vivo.

Candidate profile

M.Sc. (Mgr.) degree or equivalent in (bio)chemistry, molecular/cellular biology, neuroscience, physiology or medicine; strong interest in conducting pre-clinical research in the field of glutamate receptors.

Suggested reading

  • Svobodova et al. Int J Mol Sci. 24(11):9124 (2023).
  • Kortus et al. J Neurosci. 43(26):4755-4774 (2023).
  • Kolcheva et al., Neuropharmacology 189:108528 (2021).
  • Gorecki et al., Eur J Med Chem 219:113434 (2021).
  • Kaniakova et al., Biochem Pharmacol 186:114460 (2021).
  • Hemelikova et al., Neuropharmacology 157:107671 (2019).
  • Kaniakova et al., Curr Alzheimer Res 16(9):821-833 (2019).
  • Kaniakova et al., Neuropharmacology 140:217-232 (2018).
  • Gazova et al., Biochim Biophys Acta Mol Basis Dis 1863(2):607-619 (2017).
  • Horak et al., Prog Neuropsychopharmacol Biol Psychiatry 75:54-62 (2017).

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