316362-85-3Relevant academic research and scientific papers
Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease
Bolea, Irene,Juárez-Jiménez, Jordi,De Los Ríos, Cristóbal,Chioua, Mourad,Pouplana, Ramón,Luque, F. Javier,Unzeta, Mercedes,Marco-Contelles, José,Samadi, Abdelouahid
, p. 8251 - 8270 (2012/02/14)
A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2- yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 ± 1.1 nM) and MAO-B (IC50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 ± 0.01 μM) and BuChE (IC50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. (Figure presented)
Synthesis of new cardioselective M2 muscarinic receptor antagonists
Mandelli, Giacomina R.,Maiorana, Stefano,Terni, Patrizia,Lamperti, Giuseppina,Colibretti, Maria Luisa,Imbimbo, Bruno P.
, p. 1611 - 1622 (2007/10/03)
A series of 5H-dibenz[b,f]azepine derivatives was prepared and evaluated for binding affinities to muscarinic receptors in vitro. Among them, compound 8 showed a high affinity for human recombinant M2 receptors (K(i)=2.6 nM), a low affinity for M4 receptors (39-fold less than for M2 receptors) and a very low affinity for M1 and M3 receptors (119- and 112-fold less than for M2 receptors, respectively). The high M2 selectivity of 8 may be attributed to the olefinic bond of the azepine ring. Functional experiments showed 8 to be a competitive antagonist with high affinity to the cardiac (pA2=7.1) and low affinity to the intestinal muscarinic receptors (IC50=0.54 μM). In vivo experiments confirmed the in vitro M2 selectivity of 8. Acetylcholine-induced bradycardia was dose-dependently antagonized in rats after both intravenous and intraduodenal administration of 8. In rats, cholinergic functions mediated by M1 or M3 receptors (salivary secretion, pupil diameter, gastric emptying, intestinal transit time) were not affected by the oral administration of 8 even at doses as high as 30 times the antibradycardic effective dose. Furthermore, 8 had no analgesic activity in mice, indicating poor central nervous system penetration. In dogs, nocturnal bradycardia was dose-dependently inhibited by the oral route with a duration of action of about 24h. Compound 8 appears to be a promising cardioselective antimuscarinic agent for the treatment of dysfunctions of the cardiac conduction system such as sinus or nodal bradycardia ('sick-sinus syndrome') and atrioventricular block.
