Interaction of charged and uncharged calcium channel antagonists with phospholipid membranes. Binding equilibrium, binding enthalpy, and membrane location.
The membrane location and the binding mechanism of two Ca2+ channel antagonists, amlodipine and nimodipine, in pure lipid membranes were investigated with deuterium and phosphorus-31 nuclear magnetic resonance, with thermodynamic methods such as high-sensitivity titration calorimetry, and by measuring the membrane surface charge via the zeta-potential. The two drugs exhibit quite different physical-chemical properties. The noncharged nimodipine is strongly hydrophobic, and selective deuteration of the lipid membrane reveals a homogeneous distribution of nimodipine across the whole hydrocarbon layer, but no interaction at the lipid headgroup level. The membrane behavior of the amiphiphilic amlodipine (electric charge z = +1) is distinctly more complex. Deuterium magnetic resonance demonstrates that amlodipine adopts a well-defined position in the bilayer membrane. In particular, the charged ethanolamine side group of amlodipine is located near the water-lipid interface, interacting with the dipoles of the headgroup region according to a nonspecific, electrostatic mechanism and inducing a reorientation of the phosphocholine dipoles toward the water phase. At the level of the hydrocarbon segment, the nonpolar ring system of amlodipine interacts specifically with the cis double bond of the membrane lipid, forming a weak association complex. With increasing amlodipine concentration the deuterium signal of the cis double bond gradually loses intensity, a phenomenon previously observed only in related studies on protein-lipid interactions. The binding equilibrium of amlodipine to phosphatidylcholine membranes was studied by measuring the electrophoretic mobility of lipid vesicles and with a centrifugation assay. Hydrophobic interactions of the nonpolar ring systems and electrostatic repulsions at the membrane surface contribute to the binding energy.(ABSTRACT TRUNCATED AT 250 WORDS)
Bäuerle
H D
HD
Department of Biophysical Chemistry, University of Basel, Switzerland.
Seelig
J
J
D017311:Amlodipine; D002121:Calcium Channel Blockers / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000378:metabolism* / Q000502:physiology; D008564:Membrane Potentials; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism; D009553:Nimodipine / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism* / Q000502:physiology; D010759:Phosphorus Isotopes; D013816:Thermodynamics
D002121:Calcium Channel Blockers; D008563:Membrane Lipids; D010743:Phospholipids; D010759:Phosphorus Isotopes; D017311:Amlodipine; D009553:Nimodipine; D009543:Nifedipine