Kan KK

References (4)

Title : The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine - Yu_2008_J.Pharm.Biomed.Anal_46_75
Author(s) : Yu H , Li WM , Kan KK , Ho JM , Carlier PR , Pang YP , Gu ZM , Zhong Z , Chan K , Wang YT , Han YF
Ref : J Pharm Biomed Anal , 46 :75 , 2008
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.
ESTHER : Yu_2008_J.Pharm.Biomed.Anal_46_75
PubMedSearch : Yu_2008_J.Pharm.Biomed.Anal_46_75
PubMedID: 17931815

Title : East meets West in the search for Alzheimer's therapeutics - novel dimeric inhibitors from tacrine and huperzine A - Li_2007_Curr.Alzheimer.Res_4_386
Author(s) : Li WM , Kan KK , Carlier PR , Pang YP , Han YF
Ref : Curr Alzheimer Res , 4 :386 , 2007
Abstract : Alzheimer's disease (AD) is linked to cholinergic deficiency and the overactivation of glutamate receptors. The acetylcholinesterase (AChE) inhibition treatment approach has produced the most encouraging results in clinical practice, and memantine, a moderate antagonist of N-methyl-D-aspartate (NMDA) receptors, has been approved for treating AD. However, AChE inhibitors have limited success as they only improve memory in mild dementia but cannot stop the process of neurodegeneration; while memantine possesses neuroprotective effects only with a little ability in memory enhancement. There has been a major rush among neuroscience research institutions and pharmaceutical firms worldwide to search for safer and more effective therapeutic agents for AD. The novel dimers, derived from tacrine and the fragment of huperzine A (HA'), have been demonstrated to be potent and selective reversible inhibitors of AChE. Bis(7)-tacrine, bis(12)-hupyridone (E12E) and HA'(10)-tacrine, are representatives of three series of novel dimers. According to the preclinical studies, these compounds have been shown to have low toxicity and high efficacy for improving cognitive deficits in several animal models. More interestingly, bis(7)-tacrine, similar to memantine, prevents glutamate-induced neurotoxicity by moderately blocking glutamate receptor NMDA subtype. Furthermore, bis(7)-tacrine, as well as E12E, possesses multiple neuroprotective effects in vitro and in vivo. Taking together, these dimeric AChE inhibitors, especially bis(7)-tacrine, E12E and HA'(10)-tacrine, may provide beneficial effects in AD and other neurodegenerative diseases.
ESTHER : Li_2007_Curr.Alzheimer.Res_4_386
PubMedSearch : Li_2007_Curr.Alzheimer.Res_4_386
PubMedID: 17908041

Title : Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels - Fu_2006_J.Neurochem_98_1400
Author(s) : Fu H , Li W , Lao Y , Luo J , Lee NT , Kan KK , Tsang HW , Tsim KWK , Pang Y , Li Z , Chang DC , Li M , Han Y
Ref : Journal of Neurochemistry , 98 :1400 , 2006
Abstract : Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
ESTHER : Fu_2006_J.Neurochem_98_1400
PubMedSearch : Fu_2006_J.Neurochem_98_1400
PubMedID: 16771827

Title : Neuroprotection via inhibition of nitric oxide synthase by bis(7)-tacrine - Li_2006_Neuroreport_17_471
Author(s) : Li W , Lee NT , Fu H , Kan KK , Pang Y , Li M , Tsim KWK , Li X , Han Y
Ref : Neuroreport , 17 :471 , 2006
Abstract : Here we report that bis(7)-tacrine, a novel acetylcholinesterase inhibitor, exerts neuroprotective effects by inhibition of nitric oxide synthase. In cortical neurons at 12 days in vitro, bis(7)-tacrine concentration-dependently reduced cell death induced by glutamate, beta-amyloid and L-arginine, but not by nitric sodium nitroprusside. N-monomethyl-L-arginine, a nitric oxide synthase inhibitor, also prevented the former three types but not the last type of the cytotoxicity; however, nitric oxide scavengers blocked all of these insults, indicating that nitric oxide mediated these neuronal injuries. Furthermore, with nitric oxide synthase activity assays, it was found that bis(7)-tacrine not only suppressed the activation of nitric oxide synthase caused by glutamate in cortical neurons, but also directly inhibited the activity of nitric oxide synthase in vitro.
ESTHER : Li_2006_Neuroreport_17_471
PubMedSearch : Li_2006_Neuroreport_17_471
PubMedID: 16543809