The multiple-indicator dilution technique was utilized to examine the hepatic uptake of albumin-bound labeled palmitate from the portal vein blood of the pentobarbital-anesthetized dog, in a fasted state and after infusion of a variety of compounds that were expected to bind to Z protein, the cellular cytosolic protein binding free fatty acids, and their acyl-CoA derivatives. Analysis of the data indicates that after infusion of alpha-bromopalmitate, 16-bromo-9-hexadecenoate, and sulfobromophthalein sodium (which also bind to albumin), the palmitate label influx, efflux, and metabolic sequestration (removal of label from the pool of free fatty acids able to leave the cell) all increase and that, after infusion of flavaspidic acid, label efflux and metabolic sequestration increase. In vitro competitive binding studies carried out on the cellular cytosol indicat that the basis for the increase in efflux and metabolic sequestration is displacement of labeled palmitate from high affinity sites on the intracellular Z protein (which are presumably in equilibrium with and may be taken to be representative of other intracellular binding sites). These studies also suggest that increased uptake is due to similar displacement from high affinity sites on serum albumin.

Selective inhibitors of voltage-activated K(+) channels are needed for the treatment of multiple sclerosis. In this work it was discovered that porphyrins bearing 2-4 carbon alkyl ammonium side chains predominantly blocked the Kv1.1 current whilst Kv1.2 was susceptible to a porphyrin bearing polyamine side chains.

K channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2'-((5,5'(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2'carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis.

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