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Surface Activity Profiling: Predicting Blood-Brain Barrier Permeation

Explore physicochemical tool for drug design targeting CNS with amphiphilicity profiling, featuring Delta-8 technology and direct measurement of surface tension in lipid membranes.

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Surface Activity Profiling: Predicting Blood-Brain Barrier Permeation

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  1. Surface activity profiling:a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics & Biomembrane Group Institute of Biomedicine University of Helsinki Finland

  2. Challenge: What we know: • Design good physicochemistry into the molecules as early as possible. • Physicochemistry correlates with ADME/tox. Pharmocokinetics

  3. Outline • Existing assays • logP, TPSA, CACO2, PAMPA,... • Amphiphilicity through surface activity • Model justification • Physicochemical parameters obtained 3. Overview on Delta-8 technology • Features and specifications

  4. Lipid bilayers: barrier for the entry of drugs into cells by passive diffusion

  5. Ambiguous amphiphiles In order to be useful as a drug a compound • has to dissolve in water  hydrophilicity required • has to permeate lipid bilayers  lipophilicity required • Hydrophilic part e.g. carboxylic acid derivatives • Lipophilic part e.g. hydrocarbon chain

  6. Air-water interface – a good model for lipid membranes Air/water interface: Phospholipid bilayer: • Amphiphiles are strongly oriented in lipid membranes and in the air-water interface. • Partitioning into both interfaces is mainly driven by the hydrophobic effect

  7. Air-water interface: presence of multiple equilibria Air Aqueous phase Partitioning Micellization

  8. Amphiphilicity is monitored through surface tension Maximum pull technique:

  9. Looking at the hydrophobic effect in action... ~1/Kaw Slope= 1/As=dg/RTdlnc CMC

  10. Compound structure must be optimized for optimum performance. Can surface activity profiling help?

  11. Hydroxyzine Phenyl butazone CNS + - ”common” phys-chem MW 447.8 308.4 LogP 3.3 3.2 TPSA 36 41 Amphiphilicity profiling As 78 146 CMC 0.004 >0.01 Kaw 10000 1000 Importance of the interfacial area

  12. Prerequisites for passive permeation...

  13. Spatial arrangement does matter

  14. Solubility/hydrophobicity - antidepressants

  15. Solubility/hydrophobicity - antidepressants

  16. Solubility/hydrophobicity - antidepressants

  17. Solubility/hydrophobicity – antidepressants

  18. Fraction absorbed: surface excess vs logP Kiehm et al., AAPS, 2005

  19. Correlation between surface activity and PAMPA

  20. Literature for BBB-permeability P. Suomalainen et al., Surface Activity Profiling of Drugs Applied to the Prediction of Blood-Brain Barrier Permeability. J. Med.Chem., 47:1738-1788,2004. H. Fischer et al., Blood-Brain Barrier Permeation; Molecular Parameters Governing Passive Diffusion. J.Membr.Biol., 165:201-211, 1998 A.Seelig et al. A Method to Determine the Ability of Drugs to Diffuse Through the Blood-Brain Barrier. Proc. Natl.Acad.Sci., 91:68-72, 1994

  21. Delta-8 • Multichannel microtensiometer • 96-well compatible • Software controlled • Fully automated

  22. Use of standard footprint 96-well plate • 50 l per well • Optimized for surface tension measurements

  23. The core: 8 high sensitivity microbalances • Fixed to meet the positions of the wells in the 96-well plate • Maximum pull force/du Nouy technique • Probes instead of ring(s)

  24. Automated cleaning • Electric owen heating up to 1000°C

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