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. 2012 Jun 1;11(6):3382-9.
doi: 10.1021/pr300184g. Epub 2012 Apr 30.

Cellular membrane phospholipids act as a depository for quaternary amine containing drugs thus competing with the acetylcholine/nicotinic receptor

Damon Barbacci  1 , Shelley N Jackson, Ludovic Muller, Thomas Egan, Ernest K Lewis, J Albert Schultz, Amina S Woods
Affiliations

Cellular membrane phospholipids act as a depository for quaternary amine containing drugs thus competing with the acetylcholine/nicotinic receptor

Damon Barbacci et al. J Proteome Res. .

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.

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Figures

Figure 1
Figure 1
Contour plot of drift time versus m/z of non-covalent complexes of PA, PC, PE, PG, PI, PS with (a) DCM, (b) HXM, and (c) SCH.
Figure 1
Figure 1
Contour plot of drift time versus m/z of non-covalent complexes of PA, PC, PE, PG, PI, PS with (a) DCM, (b) HXM, and (c) SCH.
Figure 1
Figure 1
Contour plot of drift time versus m/z of non-covalent complexes of PA, PC, PE, PG, PI, PS with (a) DCM, (b) HXM, and (c) SCH.
Figure 2
Figure 2
Contour plot of drift time versus m/z of noncovalent complexes (NCX) of DCM with (a) GEREETEEEEEEEDEN and GEREEpTEEEEEEEDEN and (b) EDDDQSVSED and pSEDDDQpSVSED.
Figure 2
Figure 2
Contour plot of drift time versus m/z of noncovalent complexes (NCX) of DCM with (a) GEREETEEEEEEEDEN and GEREEpTEEEEEEEDEN and (b) EDDDQSVSED and pSEDDDQpSVSED.
Figure 3
Figure 3
Contour plot of drift time versus m/z of PA, PC, PE, PG, PI, PS, and DCM with (a) GEREETEEEEEEEDEN and GEREEpTEEEEEEEDEN and (b) EDDDQSVSED and pSEDDDQpSVSED.
Figure 3
Figure 3
Contour plot of drift time versus m/z of PA, PC, PE, PG, PI, PS, and DCM with (a) GEREETEEEEEEEDEN and GEREEpTEEEEEEEDEN and (b) EDDDQSVSED and pSEDDDQpSVSED.
Figure 4
Figure 4
(a) Contour plot of drift time versus m/z of PA, PC, PE, PG, PI, PS, DCM and Ach with (a) GEREETEEEEEEEDEN and GEREEpTEEEEEEEDEN and (b) EDDDQSVSED and pSEDDDQpSVSED.
Figure 4
Figure 4
(a) Contour plot of drift time versus m/z of PA, PC, PE, PG, PI, PS, DCM and Ach with (a) GEREETEEEEEEEDEN and GEREEpTEEEEEEEDEN and (b) EDDDQSVSED and pSEDDDQpSVSED.
Figure 5
Figure 5
Baseline mobility separation of THA/DCM clusters and protonated PE.
Scheme 1
Scheme 1
See this image and copyright information in PMC

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