The Pressuromodulation Effects of Small Molecules on Cells in Relation to the Molecular Size-Exclusion Limit for Facilitated Diffusion Across Cell Membrane Channel Pores into Cells

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Areproducible measure of molecular size is the van der Waals diameter (vdWD, nm) of a molecule represented as a sphere, and that of molecular philicity is the predicted alcohol-to-water partition coefficient (Log P) and the derived philicity for size ratio, Log P/vdWD (nm-1). These predicted measures have been previously applied to study the physiologic permeation thresholds for anionic, cationic, polyhydroxylated and neutral small molecule hydrophilic polar molecules entering systemic circulation across the less restrictive zona adherens inter-epithelial cell junction complex pores of gastrointestinal/pulmonary barrier epithelium, and thereafter, entering the central nervous system parenchyma across the more restrictive zona occludens inter-endothelial cell junction complex pores of the blood-brain barrier the permeation threshold for anionic and cationic small molecule hydrophiles across these barriers is lower than that for equivalently-sized neutral hydrophiles due to greater hydrophilicity for size (-Log P/vdWD) as charged and poly-hydroxylated hydrophiles interact with the cell membrane proteoglycan-rich glycocalyx around epithelium barrier junctions, rather than permeating across junctional complex pores. Therefore, both molecular size and hydrophilicity are co-determinants for the diffusion of hydrophiles across barrier inter-cellular junction pores; whereas, the vdWD is the primary determinant for more neutral hydrophiles, for which the permeation thresholds have been narrowed within an interval but remain open-ended as they do for apolar/non-polar small molecule lipophiles.

Endogenouslybiosynthesized and secreted peptide factors and cell membrane (CM) channel pore-excluded small molecule hormone-ligands to CM receptors also cross inter-cellular barriers for paracrine effects, and then pressuromodulate cells, in synergism with CM channel-permeable and subcellularly-localizing small molecules to regulate nuclear gene transcription and sub-cellular organelle function. Many CM receptor-localizing and/or CM channel-permeable subcellularly-localizing including endogenous hormones and exogenous molecules, some of toxic potential, are apolar/non-polar lipophilic small molecules. Therefore, in order to reproducibly predict the biologic potential of lipophilic small molecules, many of which are toxins/toxicants, and their biodistribution pharmacodynamics into tissue interstitial spaces including that into the brain parenchyma, the upper limit of molecular size-exclusion across the BBB inter-endothelial junction pores needs to be determined. The exact cellular molecular size-exclusion, lipophilicity and hydrophilicity limits for small molecule facilitated diffusion across cell membrane (CM) carrier-mediated transport channels into cells also need to be determined, in order to characterize the specific cellular and sub-cellular pressuromodulation effects and downstream molecular pathways involved.