COMPARISONS OF THE INTERACTION OF PROPRANOLOL AND TIMOLOL WITH MODEL AND BIOLOGICAL MEMBRANE SYSTEMS

Abstract

The nonspecific interaction of the .beta.-adrenergic blocking drugs, propranolol and timolol, with model and biological membranes was 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 (mol of drug/mol 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 and timolol with rabbit sarcoplasmic reticulum vesicles (SR) was similar to that with highly purified protein-depleted SR lipids, and DMPC above its phase transition. The association of propranolol with the SR membrane (mol of propranolol/mol of SR phospholipid) correlated with its ability to inhibit Ca uptake, whereas only a fraction of the total association of timolol with the SR membrane appeared to lead to inhibition of Ca uptake. The major nonspecific interactions of propranolol and timolol apparently with the SR membrane lipids, and the magnitude of their interactions depends on both the lipid solubility of the drug and the physical state of the fatty acyl chains of the membrane. Both propranolol and timolol appear to perturb the functional properties of the Ca pump protein in the SR membrane (inhibition of ATP-induced Ca uptake) indirectly by partitioning into the bulk lipid matrix of the SR lipid bilayer, although other sites of interaction cannot be excluded.