Comparisons of the interaction of propranolol and timolol with model and biological membrane systems

Journal Article · Thu Sep 01 04:00:00 EDT 1983 · Mol. Pharmacol.; (United States)

OSTI ID:5505194

Herbette, L; Katz, A M; Sturtevant, J M

The nonspecific interaction of the beta-adrenergic blocking drugs, propranolol and timolol, with model and biological membranes has been investigated. Radioisotope measurements of the association of these drugs with dimyristoyl lecithin (DMPC) bilayers showed that both propranolol and timolol had a significantly greater molar association (mole of drug per mole of lipid) with DMPC above its phase transition temperature than below. Timolol had a much lower molar association with DMPC as compared with propranolol both above and below the phase transition temperature. For the DMPC model membrane system, the molar association of propranolol as measured by radioisotope and inferred from calorimetric studies was similar. Neutron diffraction utilizing propranolol deuterated in the naphthalene moiety showed that the naphthalene moiety of propranolol partitions into the hydrocarbon core of the DMPC lipid bilayer, and that the charged amine side chain is most likely positioned in the aqueous phospholipid head group region. For timolol, the association as measured by radioisotope methods was apparently greater than the partitioning inferred from calorimetric studies using freezing point depression analysis, suggesting a more complex interaction of timolol as compared with propranolol with the DMPC lipid bilayer. The association of propranolol with the SR membrane (mole of propranolol per mole of SR phospholipid) correlated with its ability to inhibit calcium uptake, whereas only a fraction of the total association of timolol with the SR membrane appeared to lead to inhibition of calcium uptake. Both propranolol and timolol appear to perturb the functional properties of the calcium pump protein in the SR membrane (inhibition of ATP-induced calcium uptake) indirectly by partitioning into the bulk lipid matrix of the SR lipid bilayer, although other sites of interaction cannot be excluded.

• Research Organization: Cardiology Division, University of Connecticut, Farmington
• OSTI ID: 5505194
• Journal Information: Mol. Pharmacol.; (United States), Journal Name: Mol. Pharmacol.; (United States) Vol. 24:2; ISSN MOPMA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
ALKALINE EARTH METALS
AMINES
AUTONOMIC NERVOUS SYSTEM AGENTS
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
CALCIUM
CALORIMETRY
CELL CONSTITUENTS
CELL MEMBRANES
COHERENT SCATTERING
DEUTERIUM COMPOUNDS
DIFFRACTION
DRUGS
ELEMENTS
ESTERS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LECITHINS
LIPIDS
MEMBRANE TRANSPORT
MEMBRANES
METALS
NEUTRON DIFFRACTION
ORGANIC COMPOUNDS
ORGANIC PHOSPHORUS COMPOUNDS
PHOSPHOLIPIDS
REACTION KINETICS
SCATTERING
SYMPATHOLYTICS
TRACER TECHNIQUES