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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
Yu H.1,2; Li W.-M.2; Kan K.K.W.2; Ho J.M.K.2; Carlier P.R.3; Pang Y.-P.4; Gu Z.-M.5; Zhong Z.6; Chan K.7; Wang Y.-T.1; Han Y.-F.2
2008
Source PublicationJournal of Pharmaceutical and Biomedical Analysis
ISSN7317085
Volume46Issue:1Pages:75
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 (pKa) of the two dimers were determined by UV spectrophotometry. Both dimers were found to have two pKa values: 7.5 ± 0.1 (pKa1) and 10.0 ± 0.2 (pKa2) for B12H; and 8.7 ± 0.1 (pKa1) and 10.7 ± 0.4 (pKa2) 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. © 2007 Elsevier B.V. All rights reserved.

KeywordAche Inhibition Bis(12)-hupyridone Bis(7)-tacrine Dimer Ionization Constant Lipophilicity Solubility
DOI10.1016/j.jpba.2007.08.027
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Analytical ; Pharmacology & Pharmacy
WOS IDWOS:000252566400010
The Source to ArticleScopus
Scopus ID2-s2.0-36749038771
Fulltext Access
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Cited Times [WOS]:34   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorWang Y.-T.; Han Y.-F.
Affiliation1.Institute of Chinese Medical Sciences, University of Macau, Macau SAR, PR China
2.Department of Biochemistry, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong SAR, PR China
3.Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA
4.Computer-Aided Molecular Design Laboratory, Mayo Clinic College of Medicine, Rochester, MN, USA
5.XenoBiotic Laboratories, Inc., Plainsboro, NJ, USA
6.School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR, PR China
7.School of Applied Sciences, University of Wolverhampton, United Kingdom
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Yu H.,Li W.-M.,Kan K.K.W.,et al. The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine[J]. Journal of Pharmaceutical and Biomedical Analysis,2008,46(1):75.
APA Yu H.,Li W.-M.,Kan K.K.W.,Ho J.M.K.,Carlier P.R.,Pang Y.-P.,Gu Z.-M.,Zhong Z.,Chan K.,Wang Y.-T.,&Han Y.-F..(2008).The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.Journal of Pharmaceutical and Biomedical Analysis,46(1),75.
MLA Yu H.,et al."The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine".Journal of Pharmaceutical and Biomedical Analysis 46.1(2008):75.
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