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Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The irreversible inhibitors are clinically important and the propargylamine moiety is of particular interest for combination into multi-target drugs (see below). In the propargylamine class, pargyline has been in clinical use longest but deprenyl (selegiline) now leads the market as adjunct therapy for Parkinson’s disease. The highly MAO A selective clorgyline and MAO B selective deprenyl are used in PET scans (Fowler et al., 2015a). It must be noted that under chronic administration of higher doses, each of these selective inactivators will inactive the other form of the enzyme (Fowler et al., 2015b).
Serotonin (5-Ht) As A Neurotransmitter In Blood Vessels
Published in Geoffrey Burnstock, Susan G. Griffith, Nonadrenergic Innervation of Blood Vessels, 2019
The uptake of 3H-5-HT by brain vessels has been studied.85, 104 This is reduced by drugs known to inhibit serotoninergic uptake mechanisms into nerves. The uptake and release of 3H-5-HT into cerebral arteries (and also into saphenous veins) has been studied in dogs.105 It was concluded from these experiments that 5-HT can be taken up by adrenergic nerve fibers in these vessels and can be released upon transmural nerve stimulation. However, the workers indicated that their data do not exclude the possibility that at least part of the 3H-5-HT taken up by the cerebral arteries may accumulate in serotoninergic nerves. The MAO inhibitor, pargyline, increases the levels of 5-HT that can be measured in rat brain micro-vessels, indicating that these vessels contain significant amounts of MAO.80 Significant levels of MAO have also been assayed in rat cerebral vessels.106 Cerebral vessels therefore appear to possess mechanisms both to take up 5-HT and to degrade it, in order to terminate its action.
Sympathetic Neurotransmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Orthostatic hypotension is a side-effect of MAO inhibitors. This fall in blood pressure is attributed to inhibition of dietary tyramine breakdown which is then converted to octopamine by dopamine-β-hydroxylase (Figure 2.7). This acts as a false transmitter producing weaker sympathetic vasoconstriction. The fall in blood pressure has been utilized with pargyline (EutonylR) which has been used as an antihypertensive agent.
Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Changjun Zhang, Yujia Zhang, Yangjing Lv, Jianan Guo, Bianbian Gao, Yi Lu, Anjie Zang, Xi Zhu, Tao Zhou, Yuanyuan Xie
According to the latency (Figure 7(B)) and distance (Figure 7(C)) to the first entry, the time (42 ± 6 vs. 8 ± 1, ####p < 0.0001) and distance (8.9 ± 1.2 vs. 2.0 ± 1.3, ####p < 0.0001) of reaching the platform of mice treated with scopolamine were significantly prolonged, indicating that the mice model of cognitive impairment has been well-established. According to the entries to target (Figure 7(A)), treatment with pargyline and memantine notably increased the entries they crossed the platform (5.3 ± 0.9 vs. 2.1 ± 0.3, #p < 0.05; 4.0 ± 0.3 vs. 2.1 ± 0.3, ####p < 0.0001). As shown in Figure 7(B), treatment with pargyline markedly improved the cognitive impairment and reduced the latency to reach the platform compared with the model group (11 ± 1 vs. 42 ± 6, ****p < 0.0001), so as memantine (13 ± 1 vs. 42 ± 6, ***p < 0.001). Furthermore, the latency to target was significantly shortened when treated with 17d (14 ± 1 vs. 42 ± 6, ***p < 0.001). In terms of the distance to the first entry (Figure 7(C)), mice of the pargyline group led to a remarkably shorter distance to the first entry (2.6 ± 0.3 vs. 8.9 ± 1.2, ****p < 0.0001). The group of 17d exhibited a comparable activity to pargyline (3.3 ± 0.3 vs. 2.6 ± 0.3).
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
The data in Table 2 show that the majority of target compounds exhibited low to moderate inhibitory activity towards both isoforms of MAO, with some excellent hints. SAR analysis revealed that the series with 7-phenoxy moiety at tacrine core, irrespective if it was allyl or propargyl derivative, could be highlighted as selective MAO-B inhibitors with excellent inhibitory properties at both tested concentrations. In particular, derivatives 7 (5% of residual MAO-B activity at 1 μM concentration), 25 (6% of residual MAO-B activity at 1 μM concentration) and 15 (8% of residual MAO-B activity at 1 μM concentration) can be classified as the best agents in the series. Therefore, all these compounds, including 7-PhOTHA, were also forwarded for determination of the IC50 values towards MAO-B. For comparative purposes, the IC50 value of pargyline (a selective MAO-B inhibitor) was determined as well. The data in Table 2 highlight target compound 15 (IC50=40 nM) as the most potent MAO-B inhibitor of the series and starting compound 7-PhOTHA (IC50=23 nM), being two- and almost four-times as active as the reference compound pargyline (IC50=80 nM).
Vitamin D attenuated 6-OHDA-induced behavioural deficits, dopamine dysmetabolism, oxidative stress, and neuro-inflammation in mice
Published in Nutritional Neuroscience, 2022
Adedamola Bayo-Olugbami, Abdulrazaq Bidemi Nafiu, Abdulbasit Amin, Olalekan Michael Ogundele, Charles C. Lee, Bamidele Victor Owoyele
Experimental Parkinsonism was achieved by slight modification of the method previously described [32]. Briefly, vehicle (saline 0.9% containing 0.02% ascorbic acid) or 3 µg of 6-OHDA was unilaterally injected once in the right striatum. Thirty minutes prior to the surgery, desipramine hydrochloride (25 mg/kg) and pargyline hydrochloride (5 mg/kg) were administered intraperitoneally (i.p.). Desipramine and pargyline were administered prior to injection of 6-hydroxydopamine to increase the selectivity (of dopaminergic neurons) and efficacy of 6-OHDA-induced lesions. Twenty minutes after the administration of the desipramine and pargyline solution, mouse was anaesthetized with ketamine/xylazine (100/20 mg/kg i.p.), and observed for absence of withdrawal and blink reflexes.