Stereospecific recognition of a spirosuccinimide type aldose reductase inhibitor (AS-3201) by plasma proteins: A significant role of specific binding by serum albumin in the improved potency and stability
| Autor: | Buichi Fujitani, Toshiyuki Negoro, Akihito Fujii, Masuo Kurono, Makoto Murata |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Stereochemistry
Serum albumin Plasma protein binding Fatty Acids Nonesterified In Vitro Techniques Ligands Binding Competitive Biochemistry chemistry.chemical_compound Stereospecificity Succinimide Aldehyde Reductase Fatty acid binding medicine Animals Humans Spiro Compounds Tissue Distribution Enzyme Inhibitors Binding site Nuclear Magnetic Resonance Biomolecular Serum Albumin Pharmacology Molecular Structure biology Hydrolysis Temperature Stereoisomerism Blood Proteins Hydrogen-Ion Concentration Human serum albumin Rats Kinetics Spectrometry Fluorescence chemistry Organ Specificity Pyrazines biology.protein Drug Binding Site Protein Binding medicine.drug |
| Zdroj: | Biochemical Pharmacology. 71:338-353 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2005.10.036 |
| Popis: | AS-3201 [(3R)-2'-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4'(1'H)-pyrrolo[1,2-a]pyrazine]-1',2,3',5(2'H)-tetrone] is a structurally novel and stereospecifically potent aldose reductase (AKR1B; EC 1.1.1.21) inhibitor, which contains a succinimide ring that undergoes ring-opening at physiological pH levels. To delineate intermolecular interactions governing its favorable pharmacokinetic profile, the interaction of AS-3201 (R-isomer) with plasma proteins, especially human serum albumin (HSA), was examined in comparison with that of the optical antipode (S-isomer). Fluorescence, kinetic, and high-performance frontal analyses showed that the R-isomer is more strongly bound than the S-isomer to sites I and II on HSA, and the R-isomer is particularly protected from hydrolysis, suggesting that the stable HSA-R-isomer complex contributes to its prolonged activity. The thermodynamic parameters for the specific binding indicated that in addition to hydrophobic interactions, hydrogen bonds contribute significantly to the R-isomer complex formation. (13)C NMR observations of the succinimide ring (5-(13)C enriched), which are sensitive to its ionization state, suggested the presence of a hydrogen bond between the R-isomer and HSA, and (19)F NMR of the pendent benzyl ring (2-(19)F) evaluated the equilibrium exchange dynamics between the specific sites. Furthermore, fatty acid binding or glycation (both are site II-oriented perturbations) inhibited the binding to one of the specific sites and reduced the stereospecificity of HSA toward the isomers, although the clinical influence of these perturbations on the R-isomer binding ratio seemed to be minor. Thus, the difference in the interaction mode at site II might be a major cause of the stereospecificity; this is discussed on the basis of putative binding modes. The present results, together with preliminary absorption and distribution profiles, provide valuable information on the stereospecific pharmacokinetic and pharmacodynamic properties of the R-isomer relevant for the therapeutic treatment of diabetic complications. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect