Synthesis and evaluation of tacrine–Huperzine a hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of alzheimer’s disease

Badı́a, Albert; Baños, Josep-Eladi; Camps, Pelayo; Contreras, Joan Picas; Görbig, Diana M.; Muñoz‐Torrero, Diego; Simon, M. A.; Vivas, Nuria M.

doi:10.1016/s0968-0896(98)00015-7

Cited by 82 publications

(35 citation statements)

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“…More bulky substituents and also the absence of substituents at this position 16 lead to less active compounds. Substitution at position 1 (R 2 ) or 3 (R 3 ) with a methyl or fluorine atom always leads to increased AChE inhibitory activity.…”

Section: Resultsmentioning

confidence: 99%

“…15 Recently, we have published the synthesis and pharmacological evaluation of several derivatives, designed by combination of the pharmacophores of huperzine A (carbobicyclic substructure) and THA (4-aminoquinoline substructure). 16 Although compound 9, which incorporated the carbobicyclic substructure of huperzine A and the 4-aminoquinoline substructure of THA, was less active than THA, the derivatives rac-19 and rac-20 (Scheme 1), lacking the ethylidene substituent at the methylene bridge, were 2-4-fold more active than THA. It is worth noting that the introduction of substituents such as alkyl, alkoxy, or oxo at the methylene bridge as well as the substitution of this bridge by an o-phenylene one or the substitution of the benzene ring of the 4-aminoquinoline moiety by a cyclopentene ring resulted in much less active compounds.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

et al. 1999

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Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

et al. 1999

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“…The huprines are a group of AChEIs [8] , which comprise hybrid compounds of the AChEIs tacrine and huperzine A (Hup A). Huprines show high selectivity and potent inhibitory actions on human AChE, both in vitro and ex vivo [8][9][10] .…”

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confidence: 99%

“…Huprines show high selectivity and potent inhibitory actions on human AChE, both in vitro and ex vivo [8][9][10] . The (-)-enantiomer of one of the huprines, huprine X (HX), binds to AChE with one of the highest affinities yet reported for a reversible AChEI, i.e.…”

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Effect of Huprine X on β-Amyloid, Synaptophysin and α7 Neuronal Nicotinic Acetylcholine Receptors in the Brain of 3xTg-AD and APPswe Transgenic Mice

et al. 2010

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Background: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer’s disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivoin two mouse models. Methods:Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 µmol/kg, i.p., 21 days) or saline at 6–7 months. Human β-amyloid (Aβ) was measured by ELISA, synaptophysin by Western blot and α7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [¹²⁵I]α-bungarotoxin autoradiography. Results: Treatment with HX reduced insoluble Aβ1–40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of α7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal α7 nAChRs in APPswe mice. Conclusion: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Aβ and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.

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“…ex Murray) Trevis. (Lycopodiaceae) (Badia et al, 1998) have suggested their potential as natural therapeutic agents to treat AD patients. Several recent reports have demonstrated protection against A-induced neurotoxicity by plant extracts, such as onji (Polygala tenuifolia Willd., Polygalaceae) (Ikeya et al, 2004), turmeric (Curcuma longa L., Zingiberaceae) (Park & Kim, 2002), and Smilax china L. (Liliaceae) (Ban et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The neuroprotective effects of traditional oriental herbal medicines against β-amyloid-induced toxicity

Park

Kim

Hong

et al. 2009

Pharmaceutical Biology

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Synthesis and evaluation of tacrine–Huperzine a hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of alzheimer’s disease

Cited by 82 publications

References 36 publications

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Effect of Huprine X on β-Amyloid, Synaptophysin and α7 Neuronal Nicotinic Acetylcholine Receptors in the Brain of 3xTg-AD and APPswe Transgenic Mice

The neuroprotective effects of traditional oriental herbal medicines against β-amyloid-induced toxicity

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