SYNTHETIC MODELS FOR TRANSMEMBRANE CHANNELS - STRUCTURAL VARIATIONS THAT ALTER CATION FLUX

Twelve novel bis- or tris(macrocyclic) compounds have been designed as models for cation-conducting channels that function in phospholipid b ilayer vesicle membranes. In general, the channel model systems have t he structure sidearm-crown-spacer-crown-spacer-crown-sidearm'', althou gh certain features have been altered from compound to compound to ass ess the structure-activity relationship. Two additional compounds have been prepared exclusively as controls. The ionophores have been incor porated into the membranes either by warming the compound with the pre formed vesicle or by incorporation during vesicle formation. The two m ethods gave identical results within experimental error. Cation flux w as assessed by two different analytical methods. In one case, the fluo rescent dye pyranine was encapsulated within vesicles containing ionop hore. Proton transport was then monitored by changes in dye fluorescen ce with time following an acid pulse. Ionophoretic activity far most o f the compounds was studied using a dynamic NMR method in which the fl ux rate of Na-23(+) through the bilayer was monitored. All NMR studies were done in conjunction with gramicidin as a control to minimize exp erimental variations from run to run. Several of the synthetic ionopho res showed cation conduction of as much as 40% of the activity of gram icidin. Apparently, small structural changes significantly altered flu x rates and two known carriers closely related to the channel formers failed to exhibit measurable transport under comparable conditions.