Cellular Membrane Phospholipids Act as a Depository for Quaternary Amine Containing Drugs thus Competing with the Acetylcholine/Nicotinic Receptor
详细信息 查看全文
- 作者：Damon Barbacci ; Shelley N. Jackson ; Ludovic Muller ; Thomas Egan ; Ernest K. Lewis ; J. Albert Schultz ; Amina S. Woods
- 刊名：Journal of Proteome Research
- 出版年：2012
- 出版时间：June 1, 2012
- 年：2012
- 卷：11
- 期：6
- 页码：3382-3389
- 全文大小：395K
- 年卷期：v.11,no.6(June 1, 2012)
- ISSN：1535-3907
文摘
We previously demonstrated that ammonium鈥?or guanidinium鈥損hosphate interactions are key to forming noncovalent complexes (NCXs) through salt bridge formation with G-protein coupled receptors (GPCR), which are immersed in the cell membrane鈥檚 lipids. The present work highlights MALDI ion mobility coupled to orthogonal time-of-flight mass spectrometry (MALDI IM oTOF MS) as a method to determine qualitative and relative quantitative affinity of drugs to form NCXs with targeted GPCRs鈥?epitopes in a model system using, bis-quaternary amine based drugs, 伪- and 尾- subunit epitopes of the nicotinic acetylcholine receptor鈥?(nAChR) and phospholipids. Bis-quaternary amines proved to have a strong affinity for all nAChR epitopes and negatively charged phospholipids, even in the presence of the physiological neurotransmitter acetylcholine. Ion mobility baseline separated isobaric phosphatidyl ethanolamine and a matrix cluster, providing an accurate estimate for phospholipid counts. Overall this technique is a powerful method for screening drugs鈥?interactions with targeted lipids and protein respectively containing quaternary amines and guanidinium moieties.