Investigator(s)
| WHO Technical Officer |
Jagdish Kaur SEARO, RA, TFI Jagdish Kaur 
|
| Principal Investigator |
Aravindhan Ganeshan Wilfred Laurier University, Waterloo, Canada Aravindhan Ganeshan
|
| Co-Investigator(s) |
Praveen Rao Perampalli University of Waterloo Praveen Rao Perampalli
|
Title(s) and abstract
| Scientific title | Characterization of Potent Nicotinic Acetylcholine Receptor Ligands: Bridging the Knowledge Gap in Tobacco Cessation |
| Public title | Characterization of Potent Nicotinic Acetylcholine Receptor Ligands: Bridging the Knowledge Gap in Smoking Cessation |
| Background | Tobacco smoking is a major preventable public health threat, leading to deadly diseases such as lung cancer, chronic obstructive pulmonary disease, cardiovascular diseases, type 2 diabetes, stroke, and asthma. It causes over 8 million deaths globally every year, with approximately 1.3 million non-smokers affected by passive smoking. In the South-East Asia region alone, smoking accounts for 3.1 million deaths annually. Given these challenges, there is a critical need to bridge the existing knowledge gap in Tobacco research to develop effective prevention and cessation strategies that can mitigate the impacts of tobacco-related illnesses. This research aims to conduct a detailed in vitro characterization of the pharmacokinetic and cytotoxicity properties, as well as the in silico receptor interactions of a select group of potent chemical agents (10-12 compounds) targeting neuronal nicotinic acetylcholine receptors (nAChRs). |
| Objectives | General objective: to comprehensively evaluate the properties of well-known ligands for nicotinic acetylcholine receptors, focusing on their pharmacokinetics, cytotoxicity and molecular interactions with the α4β2 nAChR. Specific objectives: 1: Chemical synthesis and pharmacokinetic profiling of α4β2 nAChR ligands. 2: In vitro Cytotoxicity characterization of the ligands. 3: Computational modelling of receptor binding dynamics of the ligands. |
| Study Methods | The compounds of interest will be synthesized in vitro using established organic chemistry approaches and using solid-phase or solution-phase synthesis techniques that will be tailored to suit the specific chemical structures. The medicinal chemistry approaches will be optimized by selecting appropriate reaction pathways, reagents and conditions to ensure optimal purity and yield of compounds. To evaluate the cytotoxic effects of the identified compounds against α4β2 nAChR, the MTT assay will be employed. This assay assesses cell viability based on the reduction of the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) by mitochondrial dehydrogenases, resulting in the formation of formazan crystals, which can be quantified by measuring UV absorbance at 570 nm. The resulting ligand-nAChR complexes will be prepared under membrane-embedded physiological conditions (as described above) and subjected to MD simulations (for 100-200 ns each), and the molecular trajectories will be used to comp |
| Expected outcomes and use of results | 1. A selection of promising ligands will be identified for further evaluation based on their favorable pharmacokinetic properties. 2. A detailed report on cytotoxicity testing, documenting the concentration-response curves for each ligand and the corresponding cell viability percentages. 3. Enhanced understanding of how various ligands interact with the receptor, guiding further experimental validation and therapeutic development. |
| Keywords | smoking, tobacco, nicotine, cessation |
Research Details
| Student research | No |
| Start Date | 15-Nov-2024 |
| End Date | 15-Dec-2025 |
| Key Implementing Institution | Wilfred Laurier University |
| Multi-country research | No |
| Nationwide research | No |
| South-East Asia | |
| Research Domain(s) | Non-communicable diseases & Healthy Lifestyles |
| Research field(s) | Non-communicable Disease |
| Involves human subjects | No |
| Data Collection | Primary data |
| Proposal reviewed by other Committee | No |