Boosting Synaptic Transmission with Pyridine and Nicotinamide Derivatives – B-PaNDa

Duration: 5 Dec 2025 – 4 Dec 2028

Funding: 200,000.00 €

Summary
In the proposed project, we aim to investigate the use of newly synthesized compounds based on pyridine and nicotinamide structures (3-hydroxy-2-pyridines and derivatives of vitamins B6 and B3) as bioactive agents in modulating neurotransmission. This initiative builds naturally upon the intriguing findings regarding neuromodulatory effects at the cellular level of these compounds, which we previously identified during research funded by our Installation grant titled ”Molecular mechanisms underlying the toxicity of antidotes and potential drugs” (HrZZ-UIP-2017-05-7260). To address the central question of our project, we will I. assess the compounds’ potential to serve as agonists or antagonists at key signal-transduction receptors involved in fast-synaptic neurotransmission (nicotinic acetylcholine receptor (nAChR), N-methyl-D-aspartate receptors (NMDAR) or a-amino-3-hydroxy-5-methylisoxazolepropionic acid receptor (AMPAR) and 5-hydroxytryptamine receptors (5-HT3)); II. assess the compounds’ ability to inhibit monoamine oxidase (MAO-A and MAO-B), enzymes critical for the breakdown of neurotransmitters such as serotonin, noradrenaline, and adrenaline; and III. explore the compounds’ potential to cross blood-brain barrier and act in the central nervous system. In addition to our three primary objectives, the compounds under study will undergo profiling for cytotoxicity, myotoxicity, and genotoxicity to eliminate those with potential adverse effects to minimize the cost of subsequent preclinical studies. Utilizing the gathered data, structure-activity relationship studies and a medicinal chemistry approach will be employed to design new compounds with enhanced efficacy, selectivity, and safety profiles. This comprehensive, multidisciplinary approach will allow us to better understand the overall activity of our compounds in cholinergic, glutamatergic, and serotonergic systems and their profiles as future drugs in neurotransmission modulation.