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Interactions between β2-adrenoceptor Ligands and Membrane: Atomic-level Insights from Magic Angle Spinning NMR

Yan, Si and Shaw, Duncan and Sandham, David and Healy, Mark and Reilly, John and Wang, Bing (2017) Interactions between β2-adrenoceptor Ligands and Membrane: Atomic-level Insights from Magic Angle Spinning NMR. Journal of Medicinal Chemistry, 60 (16). pp. 6867-6879. ISSN 0022-26231520-4804

Abstract

To understand the relationship between the structural properties of the β2-adrenoceptor ligands and their interactions with membranes, we have investigated the location and distribution of five β2 agonists with distinct clinical durations of action (indacaterol, two indacaterol analogues, salmeterol and formoterol) in monounsaturated model membranes. We have used magic angle spinning NMR to quantitatively measure these interactions through 1H nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic aromatic groups of all five β2 agonists show maximum distribution in the lipid/water interface, but distinct location and dynamic behavior were observed for aromatic rings in the lipophilic regions of these compounds. The study of NOE cross-relaxation rates demonstrates the salmeterol lipophilic aromatic ring has less localization specificity than the other β2 agonists. The lipophilic aromatic rings of indacaterol, two indacaterol analogues and formoterol locate in close proximity to the upper acyl chains of the phospholipid membrane, but the diethyl groups attached to the lipophilic aromatic ring of indacaterol mostly distribute at the unsaturated bond region of the lipid membrane, much deeper toward the hydrophobic region of the membrane than the diethyl groups of its analogue (IA-2) and the methoxy group of formoterol. Our study elucidates at atomic level that the hydrophobicity and geometry of substituents on the lipophilic portion of drug molecules play important roles in compound-lipid interactions.

Item Type: Article
Date Deposited: 26 Dec 2017 00:45
Last Modified: 26 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/31261

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