MAO Inhibitors Research Articles

Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.

Background(Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises.ObjectiveOur objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not.MethodsThis was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation.ResultsOur analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and −8.84 ± 11.31 mmHg in those who did not (TCP−). Changes in DBP were −2.81 ± 11.20 mmHg for TCP+ and −10.77 ± 9.13 mmHg for TCP−. Moreover, we found a significant dose–response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12–0.60, p = 0.004; adjusted R2 = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06–0.36, p = 0.007; adjusted R2 = 0.08; p = 0.023).ConclusionsAlthough statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose–response relationship calls for caution with higher doses of tranylcypromine.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00837-6.

Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M4 Receptor Antagonism by Tanshinone I.

Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson’s disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC50 less than 10 µM. They also suppressed hMAO-B activity, with an IC50 below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M4 antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.

Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies

BackgroundDehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo.MethodThe binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography–mass spectrometry.ResultsDHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly (p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential.ConclusionDHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.

Synthesis of N′-(4-/3-/2-/Non-substituted benzylidene)-4-[(4-methylphenyl)sulfonyloxy] Benzohydrazides and Evaluation of Their Inhibitory Activities against Monoamine Oxidases and β-Secretase

Nineteen tosylated acyl hydrazone derivatives were synthesized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) were evaluated. Compound 3o was the most potent inhibitor of MAO-A, with an IC50 value of 1.54 µM, followed by 3a (IC50 = 3.35 µM). A structural comparison with 3a indicated that the 3-F group in 3o increased its inhibitory activity against MAO-A. Compound 3s was the most potent inhibitor of MAO-B, with an IC50 value of 3.64 µM, followed by 3t (IC50 = 5.69 µM). The MAO-B inhibitory activity increased in the order of 3- &gt; 4- &gt; 2-NO2 groups in 3s, 3t, and 3r, respectively. All the compounds weakly inhibited AChE and BChE, which retained &gt;50% residual activity at 10 µM, except for 3a, which inhibited BChE with an IC50 value of 16.1 µM. Interestingly, 3e, 3f, and 3n inhibited BACE-1 with IC50 values of 8.63, 9.92, and 8.47 µM, respectively, which were lower than the IC50 of the quercetin reference. Compounds 3o and 3s were found to be reversible competitive inhibitors of MAO-A and MAO-B, respectively, with Ki values of 0.35 ± 0.074 and 1.97 ± 0.65 µM, respectively. Moreover, compounds 3e, 3f, and 3n were effective BACE-1 inhibitors. The lead molecules were further investigated by molecular docking studies to elucidate the binding interactions with the target enzymes.

Participation of glutamatergic and nitrergic systems in the striatal dopamine release induced by isatin, a MAO inhibitor.

Isatin is a biofactor with different biochemical and pharmacological properties whose effects attract much attention because it is an endogenous inhibitor of the monoamine oxidase in the brain. When exogenously administrated, isatin increases dopamine levels in intact and denervated striatum of rats, an effect that could indicate its potential as a therapeutic agent in Parkinson disease. However, the neurochemical mechanisms by which isatin increases dopamine in the striatum are poorly understood. In the present study, we evaluate the role of the glutamatergic and nitrergic systems in the isatin-induced dopamine release from rat striatum. Our findings show that the intrastriatal administration of 10mM isatin significantly increases the in vivo release of dopamine (1,104.7%±97.1%), and the amino acids glutamate (428.7%±127%) and taurine (221%±22%) from rat striatum measured by brain microdialysis. The pretreatment with MK-801 (500µM) or AP5 (650µM) (glutamatergic NMDA receptors antagonists) significantly reduces the effect of isatin on dopamine release by 52% and 70.5%, respectively. The administration of the nitric oxide synthase inhibitors, L-NAME (100µM) or 7-NI (100µM) also decreases the isatin-induced dopamine release by 77% and 42%, respectively. These results show that isatin, in addition to increasing dopamine release, also increases glutamate levels, and possibly activates NMDA receptors and nitric oxide production, which can promote a further increase in the dopamine release.

Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

Occurrence, Formation from d-Fructose and 3-Deoxyglucosone, and Activity of the Carbohydrate-Derived β-Carbolines in Foods

β-Carbolines are naturally occurring bioactive alkaloids. In this work, carbohydrate-derived β-carbolines (βCs), 1-(1,3,4,5-tetrahydroxypent-1-yl)-β-carboline isomers (1a/b), 1-(1,4,5-trihydroxypent-1-yl)-β-carboline (2), 1-(1,5-dihydroxypent-3-en-1-yl)-β-carboline (3), and 1-(1,2,3,4,5-pentahydroxypent-1-yl)-β-carboline (4) were identified and analyzed in commercial foods. The concentrations of βCs 1–4 in foods ranged from undetectable to 11.4 μg/g levels, suggesting their intake in the diet. Processed foods contained higher amounts than fresh or unprocessed foods, and the highest content was found in processed tomato and fruit products, sauces, and baked foods. βCs 1–3 were formed in foods during heating, and 1a/b were the main compounds. The formation of carbohydrate-derived βCs was studied in model reactions of tryptophan and carbohydrates. They formed in reactions of tryptophan with glucose under acidic conditions at temperatures higher than 80 °C. The formation of 1a/b was favored, but 2–3 increased at high temperatures. Noticeably, the βCs 1–3 formed in the reactions of tryptophan with fructose or sucrose, and the formation from fructose was much higher than from glucose. Thus, fructose was the main carbohydrate involved in the formation of 1–3, whereas sucrose gave these βCs after acid hydrolysis. It is shown for the first time that the mechanism of formation of βCs 1–3 occurs from the sugar intermediate 3-deoxyglucosone that reacts with tryptophan affording these carbohydrate-derived βCs. A mechanism of reaction to give βCs 1–3 is proposed that relies on the tautomerism (keto–enediol or enamine–imine) of intermediates involved in the reaction. Carbohydrate βCs 1–4 were assessed as inhibitors of monoamine oxidase (MAO), as antioxidants, and for their interaction with DNA. They were not good inhibitors of MAO-A or -B, were poor antioxidants, and did not appreciably interact with DNA.

Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors.

Chalcones with methoxy substituent are considered as a promising framework for the inhibition of monoamine oxidase (MAO) enzymes. A series of nine trimethoxy substituted chalcones (TMa-TMi) was synthesized and evaluated as a multifunctional class of MAO inhibitors. All the synthesized compounds were investigated for their in vitro MAO inhibition, kinetics, reversibility, blood-brain barrier (BBB) permeation, and cytotoxicity and antioxidant potentials. In the present study, compound (2E)-3-(4-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one (TMf) was provided with a MAO-A inhibition constant value equal to 3.47±0.09 μM with a selectivity of 0.008, thus comparable to that of moclobemide, a well known potent hMAOA inhibitor (SI=0.010). Compound (2E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2- en-1-one (TMh) show good MAO-B inhibition with inhibition constant of 0.46±0.009 μM. The PAMPA assay demonstrated that all the synthesized derivatives can cross the BBB successfully. The cytotoxicity studies revealed that TMf and TMh have 88.22 and 80.18 % cell viability at 25 μM. Compound TMf appeared as the most promising antioxidant molecule with IC50 values, relative to DPPH and H2O2 radical activities equal to 6.02±0.17 and 7.25±0.07 μM. To shed light on the molecular interactions of TMf and TMh towards MAO-A and MAO-B, molecular docking simulations and MM/GBSA calculations have been carried out. The lead molecules TMf and TMh with multi-functional nature can be further employed for the treatment of various neurodegenerative disorders and depressive states.

Synthesis of new hydrazone derivatives and evaluation of their monoamine oxidase inhibitory activity

A novel series of hydrazone derivatives were designed and synthesized. Their structures were characterized by IR, 1H NMR, 13C NMR and HR-MS spectroscopic methods. The newly synthesized compounds were evaluated for their inhibitory activity against monoamine oxidase enzymes (MAO-A and MAO-B). Compounds 2a, 2k, 4a and 4i showed significant inhibitory activity against MAO-A, with IC50 value in the range of 0.084–0.207 µM compared to reference drug moclobemide (IC50 value = 6.061 µM). These compounds (2a, 2k, 4a and 4i) were exposed to cytotoxicity tests to establish their preliminary toxicological profiles and were found to be non-cytotoxic. Moreover, the most effective compound 4i was evaluated using enzyme kinetics and docking studies to elucidate the plausible mechanisms of inhibition of MAO-A. According to enzyme kinetic studies, compound 4i was a reversible and competitive inhibitor with similar inhibition features as the substrates. Also, it was seen that this compound was settled down very properly at the active site of MAO-A enzyme by doing important interactions owing to the docking studies. Finally, ADME predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. According to calculated ADME predictions, all parameters of the compounds were within the standard ranges in terms of “Rule of Five” and “Rule of Three” and it was detected that the synthesized compounds (2a-4i) have good and promising pharmacokinetic profiles.

The role of uptake and degradation in the regulation of peripheral serotonin dynamics in Gulf toadfish, Opsanus beta

The neurotransmitter serotonin (5-hyroxytryptamine, 5-HT) is involved in a variety of peripheral processes. Arguably most notable is its role as a circulating vasoconstrictor in the plasma of vertebrates. Plasma 5-HT is maintained at constant levels under normal conditions through the processes of cellular uptake, degradation, and excretion, known collectively as clearance. However, the degree to which each individual component of clearance contributes to this whole animal response remains poorly understood. The goal of this experiment was to determine the extent to which transporter-mediated uptake and intracellular degradation contribute to 5-HT clearance in the model teleost Gulf toadfish (Opsanus beta). Fish that were treated with the 5-HT transport inhibitors fluoxetine, buproprion, and decynium-22 had 1.47-fold higher plasma 5-HT concentrations and a 40% decrease in clearance rate compared to control fish. In contrast, fish treated with the MAO inhibitor clorgyline had a 1.54-fold increase in plasma 5-HT with no change in clearance rate. The results show that transporter-mediated 5-HT uptake plays an important role in controlling circulating 5-HT and whole body 5-HT homeostasis.

Nonclinical Evaluation of Antibacterial Oxazolidinones Contezolid and Contezolid Acefosamil with Low Serotonergic Neurotoxicity.

Linezolid, the principal oxazolidinone antibiotic for therapy of Gram-positive infections, is limited by its myelosuppression and monoamine oxidase (MAO) inhibition, with the latter manifested as serotonergic neurotoxicity. The oral oxazolidinone contezolid and its injectable prodrug contezolid acefosamil are developed to overcome the above limitations. Serotonergic profiles for contezolid in vitro and for orally administered contezolid acefosamil in rodents are reported. Contezolid exhibited 2- and 148-fold reduction over linezolid reversible inhibition of MAO-A and MAO-B human enzyme isoforms. In the mouse head-twitch model, contezolid acefosamil was devoid of neurotoxicity at supratherapeutic oral doses of 40, 80, and 120 mg/kg. In the rat tyramine challenge model, no significant increase in arterial blood pressure was observed for contezolid acefosamil up to 120 mg/kg oral dosing. In these tests, the comparator linezolid has elicited serotonergic responses. Thus, contezolid and contezolid acefosamil exhibited an attenuated propensity to induce MAO-related serotonergic neurotoxicity. The data support a continued clinical evaluation of these agents, with potential to expand oxazolidinone therapies to patient populations on concurrent selective serotonin reuptake inhibitor medications or where MAO inhibitors are contraindicated.

Enantioselective Interactions of Anti-Infective 8-Aminoquinoline Therapeutics with Human Monoamine Oxidases A and B.

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and -B. NPC1161B, the (R)-(−) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and -B. Racemic PQ and (R)-(−)-PQ both showed marginally greater (1.2- and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, (S)-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The (S)-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and -B compared to the (R)-(−) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics.

Slimming using magistral formulas: what are the risks?

Introduction Magistral formulas (MF) are prepared by the pharmacist for a given patient according to a prescription and following technical and scientific compounding standards. MF are often used in weight loss regimens and contain blends of drugs (D) and plant (P) extracts. Associations potentiate interactions and related adverse effects, compromising effectiveness and risking the patient’s health [1,2]. Thus, the purpose of this work is to give an overview of MF intended for slimming, prescribed by doctors, in a perspective of efficacy and safety. Materials and methods Slimming MF (prescribed to overweight women, as hard gelatine capsules, once or twice daily) were obtained in pharmacies and analysed in terms of labelled drug/bioactive composition and dosage, therapeutic indication/claim, recommended daily dose (RDD), side effects/interactions and contraindications. Written consent for data use was obtained. Results MF did not contain unlawful ingredients [3]. Actives were used mostly in sub therapeutic doses (Table 1). Weight loss is a result of (a) side effect of D-III/IV (off-label use), (b) water loss due to therapeutic action (D-I/IX and P-V/VII/VIII), or (c) claimed appetite reduction (P-VI/X/XI). Table 1. MF labels composition and dose (mg). Active ingredient (AI) MF1 MF2 MF3 MF4 MF5 MF6 MF7 Main therapeutic indication / claim Usual posology in major pathology FurosemideI 20 25 18 18 30 Diuretic 20–80/120 mg/day ChlordiazepoxideII 8 8 8 8 10 Anxiolytic 30 mg (3 times/day) BupropionIII 120 100 140 150 130 Antidepressant 150 mg (2 times/day) MetformineIV 280 250 300 300 260 Antidiabetic 500 mg (2/3 times/day) ArtichokeV 110 400 Laxative 500 mg/day* Bitter orange (Citrus aurantium) VI 150 200 200 200 200 Appetite reducer 50–100 mg/day* Centella asiatica L.VII 400 400 750 Anti-cellulite, venotonic 60–120 mg/day* Cascara Sagrada (R. purshiana)VIII 100 130 120 Laxative 150–325 mg/day* PhenolphthaleinIX 65 100 90 85 Laxative 30–200 mg/day Glucomannan (A. konjac)X 500 Appetite reducer 1000–13,000 mg/day* Slimalluma (Caralluma fimbriata) XI 300 250 Appetite reducer 500 mg (2 times/day)* Roman superscripts identify the substance in the text. *RDD not well established. Discussion and conclusions Off-label uses of drugs and efficacy of sub therapeutic doses are questionable. D-II,III present risk of abuse and dependence. Combination of laxatives (MF 1, 2 and 6) is not recommended, increasing the chances of electrolyte imbalance and dehydration, and reducing absorption of ansa diuretics. Clinical data to support the claims and posology of botanicals is scarce and contradictory; moreover, potential side effects/interactions are at times unknown and adulteration/contamination is a risk. Of note is the potential for interaction of P-V (inhibiting several isoenzymes of CYP450) and the association of D-I/P-V may cause hypovolemia and hypocaliemia. Even if no additional interactions were found between molecules, combinations may increase the risk of adverse events. Severe/fatal interactions may occur with other drugs (e.g. D-II + opioids; D-III + MAO inhibitors), so knowledge of patient's clinical history and related medication is of the utmost importance, when prescribing and counselling. Indeed, evaluation of safety and efficacy of MF is a shared responsibility of doctor and pharmacist and requires robust scientific data, especially regarding botanicals. Slimming medication alone, without lifestyle changes, is not effective in the long term and may pose a health risk, as pointed out in this study.

Sexual and reproductive health: the science behind supplementation in aging

Introduction Throughout lifespan people are increasingly committed to take control of their own health and well-being, including fertility and sexual enhancement. Food supplements (FS) industry specifically caters for this segment market. However, FS are not medicines and thus, are not subject to the same strict regulations. Misbranded, unsafe and unlawful products are on the market [1], claiming scientifically unsubstantiated benefits, without disclosing potential side effects [2] and/or interactions [3], thus representing a public health hazard. The purpose of this work was to give an overview of the main FS intended for male and female sexual performance and reproductive health, available in Portugal. Materials and methods Consumption data in pharmacies (2015–2018) was provided by ANF and inclusion criteria was FS which sold >1000 units/year. Formulas were analysed, to address the alleged bioactive substances, in a perspective of efficacy and safety. Results Overall consumption of the FS studied has risen 48% in the years analysed and target mainly the male population (≈70% of products), although there are brands specifically designed for women. Botanicals, isolated or combined, used for sexual performance problems, such as erectile dysfunction and low sexual desire, mostly claim to: (a) improve genital blood flow [vasodilators as Pausinystalia macroceras, Ferula asafoetida L., Pinus pinaster, Gingko biloba, Epimedium grandiflorum L.], (b) increase testosterone levels [Withania somnifera, Tribulus terrestris, Maca- Lepidium meyenii], or (c) act as tonics/stimulants [Eleutherococcus senticosus, Panax ginseng, Turnera diffusa, guarana]. Plant extracts are at times associated with vitamins (A,D,E,C, folic acid), minerals (Zn, Se, Fe, Mg) and amino acids (arginine aspartate, L-carnitine). For fertility/climacterium associated symptoms, DHA, EPA, lycopene and CoQ10 are also found. Discussion and conclusions Scientific evidence to support the claims of sexual enhancement is low/medium for all the plants, which however are not without harm. There is lack of studies in humans, no established daily doses and many of the side effects (e.g. severe hepatotoxicity of genus Pausinystalia; estrogen-like effect of Maca in gynaecological cancers) are not well documented. Associations of bioactives are common and increase the potential of side effects/toxicity and should be avoided. Relevant interactions with drugs [e.g. MAO inhibitors with Pausinystalia and P. ginseng; anticoagulants (e.g. warfarin) with P. maritima, P. ginseng, E. senticosus, G. biloba, F. asafoetida, E. grandiflorum; antihypertensive drugs with T. terrestris, F. asafoetida, E. grandiflorum, W. somnifera and Pausinystalia] are also possible, especially in case of polymedicated aging consumers. Moreover, since potentially harmful active pharmaceuticals, or its analogs, continue to be identified in FS, consumers should be aware of the risk in which they incur. Informed counselling by health-professionals is thus of the utmost importance and the subject should be taught to doctors, pharmacists, nutritionists and nurses.

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2

Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer

Despite increasing options for treatment of castration-resistant prostate cancer, development of drug resistance is inevitable. The glucocorticoid receptor (GR) is a prime suspect for acquired therapy resistance, as prostate cancer (PCa) cells are able to increase GR signaling during anti-androgen therapy and thereby circumvent androgen receptor (AR)-blockade and cell death. As standard AR-directed therapies fail to block the GR and GR inhibitors might result in intolerable side effects, the identification of GR signature genes, which are better suited for a targeted approach, is of clinical importance. Therefore, the specific epithelial and stromal GR signature was determined in cancer-associated fibroblasts as well as in abiraterone and enzalutamide-resistant cells after glucocorticoid (GC) treatment. Microarray and ChIP analysis identified MAO-A as a directly up-regulated mutual epithelial and stromal GR target, which is induced after GC treatment and during PCa progression. Elevated MAO-A levels were confirmed in in vitro cell models, in primary tissue cultures after GC treatment, and in patients after neoadjuvant chemotherapy with GCs. MAO-A expression correlates with GR/AR activity as well as with a reduced progression-free survival. Pharmacological MAO-A inhibition combined with 2nd generation AR signaling inhibitors or chemotherapeutics results in impaired growth of androgen-dependent, androgen-independent, and long-term anti-androgen-treated cells. In summary, these findings demonstrate that targeting MAO-A represents an innovative therapeutic strategy to synergistically block GR and AR dependent PCa cell growth and thereby overcome therapy resistance.

Water-Soluble Near-Infrared Fluorescent Probes for Specific Detection of Monoamine Oxidase A in Living Biosystems.

Monoamine oxidase (MAO) has two isomers (A and B), and the analysis of each one in biological samples is of great potential in studying MAO-related diseases. However, specific detection and imaging of MAO-A in cells and in vivo are still a great challenge at present due to the relative lack of suitable near-infrared (NIR) fluorescent probes. In this work, two new NIR fluorescent probes, Rma-1 and Rma-2, have been developed for the analysis of MAO-A in living biosystems. The probes were designed by conjugating the specific structure of the MAO-A inhibitor to hemicyanine (an NIR fluorophore) directly or through a self-immolative linker. Both probes are water-soluble and showed selective and sensitive NIR (708 nm) responses toward MAO-A rather than MAO-B, of which probe Rma-1 with a self-immolative linker exhibited superior analytical performance with a detection limit of 4.5 ng/mL and 13-fold specificity for MAO-A over MAO-B. Further, probe Rma-1 has been successfully utilized to image the MAO-A activity in cells, zebrafish, and tumor-bearing mice, showing a promising prospect for MAO-A study in carcinoma.

New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 μM, Selectivity Index (SI): 9.70 × 10-4), 7 (0.009 μM, SI: 4.55 × 10-5), 14 (0.001 μM, SI: 8.00 × 10-4), 21 (0.009 μM, SI: 1.37 × 10-5), and 42 (0.010 μM, SI: 5.40 × 10-6), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.

WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors

Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570–574, 2016) and extends it into a virtual screening tool by introducing facile experimental or computational parametrization and a ligand focused evaluation scheme together with a retrospective and prospective validation against various therapeutically relevant targets. Parameters accounting for ligand reactivity are derived from experimental reaction kinetic data or alternatively from computed reaction barriers. The performance of this docking protocol was first evaluated by investigating compound series with diverse warhead chemotypes against KRASG12C, MurA and cathepsin B. In addition, WIDOCK was challenged on larger electrophilic libraries screened against OTUB2 and NUDT7. These retrospective analyses showed high sensitivity in retrieving experimental actives, by also leading to superior ROC curves, AUC values and better enrichments than the standard covalent docking tool available in AutoDock4 when compound collections with diverse warheads were investigated. Finally, we applied WIDOCK for the prospective identification of covalent human MAO-A inhibitors acting via a new mechanism by binding to Cys323. The inhibitory activity of several predicted compounds was experimentally confirmed and the labelling of Cys323 was proved by subsequent MS/MS measurements. These findings demonstrate the usefulness of WIDOCK as a warhead-sensitive, covalent virtual screening protocol.

Candidate pharmacological treatments for substance use disorder and suicide identified by gene co-expression network-based drug repositioning.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.