Interactions between β2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR

To
understand the relationship between 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 and onsets of action (indacaterol,
two indacaterol analogues, salmeterol and formoterol) in monounsaturated
model membranes using magic angle spinning NMR to measure these interactions
through both 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 the lipophilic aromatic rings. Our study elucidates
at atomic level that the hydrophobicity and substitution geometry
of lipophilic groups play important roles in compound–lipid
interactions.