Possible targeting of G protein coupled receptors to manipulate inflammation in vivo using synthetic and natural ligands.

Cyclic AMP elevating Gs protein coupled receptors were considered for a long time to be immunosuppressive. One of these receptors, adenosine A(2A) receptor, was implicated in a physiological mechanism that down regulates inflammation and protects tissues from excessive immune mediated damage. Targeting of these receptors by selective agonists may lead to better protocols of anti-inflammatory treatments. At the same time inhibiting the Gs protein coupled mediated signalling with antagonists could be explored in studies of approaches to enhance inflammation and tissue damage. Enhancement of targeted tissue damage is highly desirable when it is cancerous tissue, while enhancement of inflammatory events might be desirable in the development of new vaccine adjuvants.

The effect of amine structure on complexation with lasalocid in model membrane systems. II. Ionophore selectivity for amines in lipid bilayers and at oil/water interfaces.

The ionophore antibiotic X-537A (lasalocid) transports biogenic amines across biological and artificial membranes. The major portion of amine flux (greater than 99%) occurs as a 1:1 neutral complex. The rank order of ionophore selectivity was determined for lipid bilayer membrane transport of amines based on a comparison of permeability coefficients: p-tyramine approximately beta-phenylethylamine approximately amphetamine greater than methamphetamine greater than dopamine greater than phenylephrine approximately metanephrine greater than norepinephrine greater than epinephrine. This rank order is in agreement with results obtained from partitioning measurements which were carried out in parallel to the bilayer membrane experiments. A correlation between amine structure and binding characteristics has been developed.

The effect of amine structure on complexation with lasalocid in model membrane systems. I. Identification of charged complexes in lipid bilayer membranes.

The electrical properties of X-537A (lasalocid) doped lipid bilayer membranes were studied in the presence of a series of nine biogenic amines which contain beta-phenylethylamine as the basic structural unit. The ionophore antibiotic was found to form charged complexes within the membrane during the transport of some of the amines. The dependence of membrane conductance on the concentration of ionophore and amine was studied. The amines are divided into three classes according to the nature of the complexes formed: (1) charged complex involving two ionophores (phenylephrine, metanephrine, and amphetamine); (2) charged complex containing three ionophores (dopamine, norepinephrine and epinephrine); and (3) no charged species formed (p- and m-tyramine and beta-phenylethylamine).