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Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Ireen Denya, Sarel F. Malan, Jacques Joubert
In a study by Li et al. (2016), a series of compounds were synthesised with a strategy to retain the benzylpiperidine fragment with ChE inhibitory properties and introduce the benzamide function of the 2-picolinamide moiety from lazabemide with MAO inhibitory capacity. The team also introduced a 2-thiophene-carboxamide moiety because of its structural similarity to benzamide and compared these to pyridine, quinoline and/or substituted phenyl moieties. SAR analysis showed that compounds with nitrophenyl- or 2-quinoline amide substitutions together with a 2C linker linked to the benzylpiperidine moiety were the most potent ChE inhibitors. The 6-methyl-2-pyridine amide with a 2C linker portrayed the best MAO IC50 values. The representative compound 1 (Fig. 11.5) possessed the best-balanced MAO and ChE activity across all the tested compounds.
Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Rani Sasidharan, Bo Hyun Eom, Jeong Hyun Heo, Jong Eun Park, Mohamed A. Abdelgawad, Arafa Musa, Nicola Gambacorta, Orazio Nicolotti, Sreedharannair Leelabaiamma Manju, Bijo Mathew, Hoon Kim
We describe the synthesis of morpholine-containing α,β-unsaturated ketones, and the results of an investigation of their MAOs and AChE inhibition profiles. Most of the nine compounds synthesised exhibited potent MAO-B inhibition with moderate AChE inhibition. Interestingly, MO1 (the lead compound) inhibited MAO-B inhibition in the low nanomolar range and was more potent than lazabemide (the reference compound). The low cytotoxicity and the ability of MO1 to transit the BBB support our drug design strategy. In addition, the ROS scavenging efficacy of MO1 suggests improved neuroprotective effects.
MAO inhibitors and their wider applications: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
Simone Carradori, Daniela Secci, Jacques P. Petzer
One nicotinamide-based derivative (23) was synthesized and characterized in order to resemble the structure of lazabemide, a selective and reversible MAO-B inhibitor (not in the market) (Figure 4) [56]. The compound displayed IC50 MAO-A = 0.044 µM and IC50 MAO-B = 26.35 µM (SI: 0.0017), but no additional data were presented.
The pharmacodynamic profile of “Blackadder” blackcurrant juice effects upon the monoamine axis in humans: A randomised controlled trial
Published in Nutritional Neuroscience, 2020
Anthony W. Watson, Arjan Scheepens, David O. Kennedy, Janine M. Cooney, Tania M. Trower, Crystal F. Haskell-Ramsay
The current study illustrates a sustained significant reduction in peripheral platelet MAO-B activity of ∼100% by consuming “Blackadder” blackcurrant when compared to control. This reduction began within 15 min of consumption, during the first post-dose epoch measured, and continued to be significantly reduced through to four hours post dose, that being the last measurement on the day of treatment. Platelet MAO-B activity had returned close to the pre-dose baseline level 24 h post dose. Due to the extremely rapid inhibition of the platelet MAO-B enzyme, it is not possible to calculate a time to maximal inhibition. It would therefore be useful if future studies were conducted using several doses and shorter initial blood collection epochs. The profile of MAO-B inhibition of “Blackadder” juice bears a notable similarity, to pharmaceutical reversible MAO-B specific inhibitors such as lazabemide, which have shown a rapid inhibition of MAO-B in platelets of >90% at 30 min post dose, with maximal inhibition subsiding 16 h post dose and full restoration of enzyme activity returning 48 h post dose following a 100 mg dose of lazabemide22. The active compound or compounds driving the inhibition in the present study are currently not known. Data in the literature outline an inhibition of MAO-B by anthocyanins in vitro23; however, this study used levels 1000 times higher than quantified in plasma after oral consumption7. In addition maximal plasma concentrations of anthocyanins do not occur until one to two hours post oral consumption24, making it unlikely that they explain the effects seen at 15 min in the current study. Coupled with the inability of a blackcurrant anthocyanin-enriched extract (DelcyanTM) to inhibit platelet MAO-B in our previous publication7, these data suggest that anthocyanins are not likely to be the compound driving MAO inhibition in vivo. However, this does not rule out a synergy between anthocyanins and lower molecular weight phenolic components such as phenolic acids. Further research needs to be conducted to attempt to identify the components responsible for the observed MAO inhibition.