title: The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.
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.
authors.affiliation: Institute of Chinese Medical Sciences, University of Macau, Macau SAR, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Li
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: Kan
authors.forename: Jason M K
authors.initials: JM
authors.lastname: Ho
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.forename: Zhe-Ming
authors.initials: ZM
authors.lastname: Gu
authors.forename: Zuo
authors.initials: Z
authors.lastname: Zhong
authors.forename: Kelvin
authors.initials: K
authors.lastname: Chan
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wang
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D002627:Chemistry, Physical / Q000379:methods* / Q000592:standards; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D019281:Dimerization; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013619:Tacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D002800:Cholinesterase Inhibitors; D015363:Quinolones; D012717:Sesquiterpenes; C528260:bis(12)-hupyridone; D013619:Tacrine