title: Cellular membrane phospholipids act as a depository for quaternary amine containing drugs thus competing with the acetylcholine/nicotinic receptor.
abstract: We previously demonstrated that ammonium- or guanidinium-phosphate 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's 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' epitopes in a model system using, bis-quaternary amine based drugs, α- and β- subunit epitopes of the nicotinic acetylcholine receptor' (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' interactions with targeted lipids and protein respectively containing quaternary amines and guanidinium moieties.
authors.affiliation: Integrative Neuroscience, NIDA IRP, NIH , Baltimore, Maryland 21224, United States.
authors.forename: Damon
authors.initials: D
authors.lastname: Barbacci
authors.forename: Shelley N
authors.initials: SN
authors.lastname: Jackson
authors.forename: Ludovic
authors.initials: L
authors.lastname: Muller
authors.forename: Thomas
authors.initials: T
authors.lastname: Egan
authors.forename: Ernest K
authors.initials: EK
authors.lastname: Lewis
authors.forename: J Albert
authors.initials: JA
authors.lastname: Schultz
authors.forename: Amina S
authors.initials: AS
authors.lastname: Woods
mesh_terms: D000109:Acetylcholine / Q000737:chemistry*; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D003650:Decamethonium Compounds / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018738:Hexamethonium / Q000737:chemistry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013390:Succinylcholine / Q000737:chemistry
chemical_list: D003650:Decamethonium Compounds; D010446:Peptide Fragments; D010743:Phospholipids; D011978:Receptors, Nicotinic; D018738:Hexamethonium; C033019:decamethonium; D013390:Succinylcholine; D000109:Acetylcholine