Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands
| Autor: | Laura Luebbert, Chengcheng Fan, Zack Blumenfeld, Aaron L Nichols, Annet EM Blom, Bruce N Cohen, Jonathan S Marvin, Philip M Borden, Charlene H Kim, Anand K Muthusamy, Amol V Shivange, Hailey J Knox, Hugo Rego Campello, Jonathan H Wang, Dennis A Dougherty, Loren L Looger, Timothy Gallagher, Douglas C Rees, Henry A Lester |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Mouse
iDrugSnFRs QH301-705.5 Science inside-out pharmacology Ligands Heterocyclic Compounds 4 or More Rings Fluorescence General Biochemistry Genetics and Molecular Biology neuroscience Substance Misuse Mice Alkaloids Heterocyclic Compounds Tobacco Animals Humans Nicotinic Agonists Biology (General) Cancer Tobacco Smoke and Health General Immunology and Microbiology General Neuroscience Neurosciences Azepines General Medicine 4 or More Rings biosensors Azocines Brain Disorders Good Health and Well Being nicotinic agonists Medicine Smoking Cessation Generic health relevance Biochemistry and Cell Biology Drug Abuse (NIDA only) pharmacokinetics Quinolizines nicotine |
| Zdroj: | eLife, Vol 11 (2022) |
| Popis: | Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug-sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives – 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by >30-fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience. |
| Databáze: | OpenAIRE |
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