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dc.contributor.authorYu, Hua
dc.contributor.authorLi, Wen-Ming
dc.contributor.authorKan, Kelvin K.
dc.contributor.authorHo, Jason
dc.contributor.authorCarlier, Paul
dc.contributor.authorPang, Yuan-Ping
dc.contributor.authorGu, Zhe-Ming
dc.contributor.authorZhong, Zuo
dc.contributor.authorChan, Kelvin C.
dc.contributor.authorWang, Yi-Tao
dc.contributor.authorHan, Yi-Fan
dc.date.accessioned2008-06-09T15:10:28Z
dc.date.available2008-06-09T15:10:28Z
dc.date.issued2008
dc.identifier.citationJournal of pharmaceutical and biomedical analysis, 46(1): 75-81
dc.identifier.issn0731-7085
dc.identifier.pmid17931815
dc.identifier.doi10.1016/j.jpba.2007.08.027
dc.identifier.urihttp://hdl.handle.net/2436/29677
dc.description.abstractThe 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 was >1.41 mg/ml when the pH was <7, but <0.06 mg/ml when the pH was >8. The solubility of B7T was >0.26 mg/ml when the pH was <9, but <0.005 mg/ml when the pH was >12. 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.
dc.language.isoen
dc.publisherAmsterdam: Elsevier
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TGX-4PK7P5N-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cd76f3d524c43665c1a55558ae7b7834
dc.subjectPharmacokinetics
dc.subjectNeuropharmacology
dc.subject.meshAdministration, Oral
dc.subject.meshAlgorithms
dc.subject.meshAlzheimer Disease
dc.subject.meshAnimals
dc.subject.meshCerebral Cortex
dc.subject.meshChemistry, Physical
dc.subject.meshCholinesterase Inhibitors
dc.subject.meshChromatography, High Pressure Liquid
dc.subject.meshDimerization
dc.subject.meshHydrogen-Ion Concentration
dc.subject.meshHydrophobicity
dc.subject.meshInjections, Intraperitoneal
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred ICR
dc.subject.meshMolecular Structure
dc.subject.meshQuinolones
dc.subject.meshSesquiterpenes
dc.subject.meshSolubility
dc.subject.meshSpectrophotometry, Ultraviolet
dc.subject.meshTacrine
dc.titleThe physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.
dc.typeJournal article
dc.identifier.journalJournal of pharmaceutical and biomedical analysis
html.description.abstractThe 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 was >1.41 mg/ml when the pH was <7, but <0.06 mg/ml when the pH was >8. The solubility of B7T was >0.26 mg/ml when the pH was <9, but <0.005 mg/ml when the pH was >12. 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.


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