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    The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.

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    Authors
    Yu, Hua
    Li, Wen-Ming
    Kan, Kelvin K.
    Ho, Jason
    Carlier, Paul
    Pang, Yuan-Ping
    Gu, Zhe-Ming
    Zhong, Zuo
    Chan, Kelvin C.
    Wang, Yi-Tao
    Han, Yi-Fan
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    Issue Date
    2008
    
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    Abstract
    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 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.
    Citation
    Journal of pharmaceutical and biomedical analysis, 46(1): 75-81
    Publisher
    Amsterdam: Elsevier
    Journal
    Journal of pharmaceutical and biomedical analysis
    URI
    http://hdl.handle.net/2436/29677
    DOI
    10.1016/j.jpba.2007.08.027
    PubMed ID
    17931815
    Additional Links
    http://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
    Type
    Journal article
    Language
    en
    ISSN
    0731-7085
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jpba.2007.08.027
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    Research Institute in Healthcare Science

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