The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine
| Autor: | Zuo Zhong, Wenming Li, Kelvin Chan, Yitao Wang, Jason M.K. Ho, Paul R. Carlier, Yifan Han, Hua Yu, Yuan Ping Pang, Zhe Ming Gu, Kelvin K.W. Kan |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
Stereochemistry Dimer Clinical Biochemistry Administration Oral Pharmaceutical Science Quinolones Medicinal chemistry High-performance liquid chromatography Acid dissociation constant Analytical Chemistry Mice chemistry.chemical_compound Alzheimer Disease Drug Discovery medicine Animals Solubility Chromatography High Pressure Liquid Spectroscopy Huperzine A Cerebral Cortex Mice Inbred ICR Molecular Structure Chemistry Physical Hydrogen-Ion Concentration chemistry Ionic strength Tacrine Lipophilicity Spectrophotometry Ultraviolet Cholinesterase Inhibitors Dimerization Hydrophobic and Hydrophilic Interactions Sesquiterpenes Algorithms Injections Intraperitoneal medicine.drug |
| Zdroj: | Journal of Pharmaceutical and Biomedical Analysis. 46:75-81 |
| ISSN: | 0731-7085 |
| DOI: | 10.1016/j.jpba.2007.08.027 |
| Popis: | The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P). The log P values for B12H and B7T were found to be 5.4 and 8.2, respectively, indicating that the two dimers are highly lipophilic. The solubilities of both dimers were found to be affected by pH. The solubility of B12H was1.41 mg/ml when the pH was7, but0.06 mg/ml when the pH was8. The solubility of B7T was0.26 mg/ml when the pH was9, but0.005 mg/ml when the pH was12. The ionic strength of a solution could affect the solubilities considerably (11.16 mg/ml for B12H and 12.71 mg/ml for B7T in water; 2.07 mg/ml for B12H and 0.36 mg/ml for B7T in saline). The ionization constants (pK(a)) of the two dimers were determined by UV spectrophotometry. Both dimers were found to have two pK(a) values: 7.5+/-0.1 (pK(a1)) and 10.0+/-0.2 (pK(a2)) for B12H; and 8.7+/-0.1 (pK(a1)) and 10.7+/-0.4 (pK(a2)) for B7T. Furthermore, an in vivo pharmacological assay conducted in mice showed that a maximum AChE inhibition occurred 15 min after the single-dose and intraperitoneal administration of either dimer. This indicates that the two dimers may easily cross the blood-brain barrier. In summary, these physiochemical characteristics suggest that the two dimers may be promising candidates for the development of better drugs for Alzheimer's disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect