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

2.50
Hdl Handle:
http://hdl.handle.net/2436/29677
Title:
The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.
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
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
Issue Date:
2008
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:
Article
Language:
en
ISSN:
0731-7085
Appears in Collections:
Pharmacy and Natural Products Research Group

Full metadata record

DC FieldValue Language
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): 75-81en
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.en
dc.language.isoenen
dc.publisherAmsterdam: Elsevieren
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=cd76f3d524c43665c1a55558ae7b7834en
dc.subjectPharmacokineticsen
dc.subjectNeuropharmacologyen
dc.subject.meshAdministration, Oralen
dc.subject.meshAlgorithmsen
dc.subject.meshAlzheimer Diseaseen
dc.subject.meshAnimalsen
dc.subject.meshCerebral Cortexen
dc.subject.meshChemistry, Physicalen
dc.subject.meshCholinesterase Inhibitorsen
dc.subject.meshChromatography, High Pressure Liquiden
dc.subject.meshDimerizationen
dc.subject.meshHydrogen-Ion Concentrationen
dc.subject.meshHydrophobicityen
dc.subject.meshInjections, Intraperitonealen
dc.subject.meshMaleen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred ICRen
dc.subject.meshMolecular Structureen
dc.subject.meshQuinolonesen
dc.subject.meshSesquiterpenesen
dc.subject.meshSolubilityen
dc.subject.meshSpectrophotometry, Ultravioleten
dc.subject.meshTacrineen
dc.titleThe physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.en
dc.typeArticleen
dc.identifier.journalJournal of pharmaceutical and biomedical analysisen

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