title: Structure-activity relationship for enhancement of paracellular permeability across Caco-2 cell monolayers by 3-alkylamido-2-alkoxypropylphosphocholines.
abstract: Paracellular permeability enhancers have been used to improve the oral bioavailability of hydrophilic drugs; however, the mechanism of action of many enhancers is poorly understood. In this study, highly potent enhancers of paracellular permeability were identified in the 3-alkylamido-2-alkoxypropylphosphocholine series, and a structure-activity relationship was developed for enhancement of paracellular permeability across Caco-2 cell monolayers. Compounds with short (<5 carbons) hydrocarbon chains at both C-2 and C-3 were generally inactive. The potency exhibited a parabolic relationship with respect to the chain length at either C-2 or C-3. Linear molecules (i.e., compounds with a short hydrocarbon chain at C-2 or C-3 and a long hydrocarbon chain on C-3 or C-2, respectively) were more potent than the corresponding branched molecules with the same carbon load. The efficacy of 3-alkylamido-2-alkoxypropylphosphocholines as enhancers of paracellular permeability was not dependent on their existence in micellar form or their ability to alter the fluidity of cell membrane. Previously, a correlation between the potency of alkylphosphocholines as enhancers of paracellular permeability and the inhibitors of phospholipase C (PLC) was established in Madine Darby canine kidney (MDCK) cell monolayers. The potencies of selected 3-alkylamido-2-alkoxypropylphosphocholines as inhibitors of PLC and enhancers of paracellular permeability fit well into this correlation. Therefore, phosphocholines are likely to increase paracellular permeability by modulating the signal transduction pathway initiated by a PLC-catalyzed reaction rather than by physically altering the cell membrane.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ouyang
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Ishaq
authors.forename: Peter
authors.initials: P
authors.lastname: Ward
authors.forename: Dongzhou
authors.initials: D
authors.lastname: Liu
authors.forename: Sarah
authors.initials: S
authors.lastname: Leonard
authors.forename: Dhiren R
authors.initials: DR
authors.lastname: Thakker
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D008353:Mannitol / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D008823:Micelles; D010539:Permeability; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019108:Tight Junctions / Q000187:drug effects; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D004963:Estrenes; D008823:Micelles; D011760:Pyrrolidinones; D010767:Phosphorylcholine; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D008353:Mannitol; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases