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The Thermodynamics of the Partitioning of Ionizing Molecules Between Aqueous Buffers and Phospholipid Membranes

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Purpose

To study the thermodynamics of partitioning of eight ionising dual D2-recepto β2-adrenoceptor agonists between vesicles of L-α-dimyristoylphosphatidylcholine (DMPC) and aqueous buffers.

Methods

The thermodynamics of partitioning have been studied by isothermal titration calorimetry (ITC).

Results

Compounds which are predominantly cationic at pH 7.4 (designated as class 1 compounds) have a more exothermic partitioning than those which are predominantly in the electronically neutral form (designated as class 2 compounds) at pH 7.4, and less positive standard entropies of partitioning. Under acidic conditions (pH 4.0), class compounds 2 (predominantly electronically neutral at pH 7.4) are almost completely cationic and accordingly have a more exothermic partitioning than at pH 7.4. The standard entropies of partitioning also depend on the pH. When the compounds are predominantly cationic, the standard entropy change is less positive (less favourable) than under conditions where the compounds are predominantly electronically neutral.

Conclusions

The observations are consistent with the notion of there being a favourable electrostatic interaction (enthalpically) between the positively charged amino-group of predominantly cationic compounds and the negatively charged phosphate group of the vesicle.

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Authors and Affiliations

  1. Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK

    Rupert P. Austin, Patrick Barton, Andrew M. Davis, Roger E. Fessey & Mark C. Wenlock

Authors
  1. Rupert P. Austin
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  2. Patrick Barton
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  3. Andrew M. Davis
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  4. Roger E. Fessey
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  5. Mark C. Wenlock
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Correspondence to Roger E. Fessey.

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Austin, R.P., Barton, P., Davis, A.M. et al. The Thermodynamics of the Partitioning of Ionizing Molecules Between Aqueous Buffers and Phospholipid Membranes. Pharm Res 22, 1649–1657 (2005). https://doi.org/10.1007/s11095-005-6336-7

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  • DOI: https://doi.org/10.1007/s11095-005-6336-7

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