151097-70-0Relevant academic research and scientific papers
Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments
?ozińska, Iwona,?wierczyńska, Aleksandra,Mol?da, Zuzanna,Hartman, Alwin M.,Hirsch, Anna K. H.,Czarnocki, Zbigniew
, (2018/10/15)
Hybrid inhibitors of acetyl- and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin–donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase.
3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof
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, (2018/09/11)
The present invention relates to a 3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof, and specifically discloses a compound represented by a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each group is defined in the specification. According to the present invention, the compound has dual inhibitory activity on acetylcholinesterase and phosphodiesterase 5, and has good blood-brain barrier permeability, such that the compound can be used for preparing drugs for treatment and/or prevention ofAlzheimer's diseases. The formula I is defined in the specification.
M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding
Keller, Max,Tr?nkle, Christian,She, Xueke,Pegoli, Andrea,Bernhardt, Günther,Buschauer, Armin,Read, Roger W.
, p. 3970 - 3990 (2015/02/19)
A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [3H]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M2 > M1 ≈ M4 > M3 ≈ M5 (46, 50, 57, 62-64) and M2 > M1 ≈ M4 > M3 > M5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M2 receptor affinities (pIC50 = 9.0 and 9.2, respectively). At the M2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC50,diss, an estimate of affinity to the allosteric site of M2 receptors occupied with [3H]NMS. Compounds 58 and 62-64 were capable of retarding [3H]NMS dissociation by a factor >10 (Emax,diss >92%), with highest potency (pEC50,diss = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC50,diss = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding.
Synthesis and evaluation of multi-target-directed ligands against Alzheimer's disease based on the fusion of donepezil and ebselen
Luo, Zonghua,Sheng, Jianfei,Sun, Yang,Lu, Chuanjun,Yan, Jun,Liu, Anqiu,Luo, Hai-Bin,Huang, Ling,Li, Xingshu
, p. 9089 - 9099 (2014/01/06)
A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min-1), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.
Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease
Samadi, Abdelouahid,Chioua, Mourad,Bolea, Irene,De Los Ríos, Cristóbal,Iriepa, Isabel,Moraleda, Ignacio,Bastida, Agatha,Esteban, Gerard,Unzeta, Mercedes,Gálvez, Enrique,Marco-Contelles, José
supporting information; experimental part, p. 4665 - 4668 (2011/11/05)
The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22-25. Compounds of type II were prepared by Friedl?nder type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1-11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC50 = 16 ± 2; Ki = 12 ± 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer's disease.
