RESUMEN

INTRODUCTION: The UK is the only permanent member of the UN Security Council that has a policy of recruiting 16 and 17 year old individuals into its regular Armed Forces. Little is known about the consequences of enlisting as a Junior Entrant (JE), although concerns have been expressed. We compare the mental health, deployment history, and pre-enlistment and post-enlistment experiences of personnel who had enlisted as JEs with personnel who joined as Standard Entrants (SEs). METHOD: Participants from a large UK military cohort study completed a self-report questionnaire between 2014 and 2016 that included symptoms of probable post-traumatic stress disorder (PTSD), common mental disorders, alcohol consumption, physical symptoms and lifetime self-harm. Data from regular non-officer participants (n=4447) from all service branches were used in the analysis. JEs were defined as having enlisted before the age of 17.5 years. A subgroup analysis of participants who had joined or commenced adult service after April 2003 was carried out. RESULTS: JEs were not more likely to deploy to Iraq or Afghanistan but were more likely to hold a combat role when they did (OR 1.25, 95% CI 1.00 to 1.56). There was no evidence of an increase in symptoms of common mental disorders, PTSD, multiple somatic symptoms (MSS), alcohol misuse or self-harm in JEs in the full sample, but there was an increase in alcohol misuse (OR 1.84, 95% CI 1.18 to 2.87), MSS (OR 1.51, 95% CI 1.04 to 2.20) and self-harm (OR 2.13, 95% CI 1.15 to 3.95) in JEs who had commenced adult service after April 2003. JEs remain in adult service for longer and do not have more difficulties when they leave service. CONCLUSIONS: JEs do not have worse mental health than SEs, but there is uncertainty in relation to alcohol misuse, MSS and self-harm in more recent joiners. Monitoring these concerns is advisable.

Asunto(s)

Alcoholismo , Personal Militar , Trastornos por Estrés Postraumático , Adulto , Humanos , Adolescente , Estudios de Cohortes , Alcoholismo/complicaciones , Alcoholismo/epidemiología , Alcoholismo/psicología , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/psicología , Reino Unido/epidemiología

RESUMEN

The covalently bound FAD cofactor in monoamine oxidase (MAO) is reduced by the amine substrate and reoxidized by oxygen. Visible spectroscopy provides a convenient tool to study the interaction of ligands and the kinetics of the half-reactions for mechanistic investigations. Equilibrium redox titrations allow measurement of redox potentials, while rapid mixing experiments allow determination of the rate of reduction by different substrates and of covalent adduct formation by irreversible inactivators. Three techniques are described: (1) measuring ligand interactions by alterations in the spectrum, especially at 495 nm; (2) reducing MAO, including the essentials for anaerobic procedures; and (3) studying kinetics of reduction, reoxidation, or inactivation of MAO.

Asunto(s)

Flavina-Adenina Dinucleótido , Monoaminooxidasa , Aminas , Flavina-Adenina Dinucleótido/metabolismo , Cinética , Ligandos , Monoaminooxidasa/metabolismo , Oxidación-Reducción , Oxígeno , Análisis Espectral

RESUMEN

BACKGROUND: Around 8% of the UK Armed Forces leave in any given year, and must navigate unfamiliar civilian systems to acquire employment, healthcare, and other necessities. This paper determines longer-term prevalences of mental ill health and socioeconomic outcomes in UK Service leavers, and how they are related to demographic factors, military history, and pre-enlistment adversity. METHODS: This study utilised data from a longitudinal sample of a cohort study UK Armed Forces personnel since 2003. A range of self-reported military and sociodemographic factors were analysed as predictors of probable Post-Traumatic Stress Disorder, common mental disorders, alcohol misuse, unemployment and financial hardship. Prevalences and odds ratios of associations between predictors and outcomes were estimated for regular veterans in this cohort. RESULTS: Veteran hardship was mostly associated with factors linked to socio-economic status: age, education, and childhood adversity. Few military-specific factors predicted mental health or socio-economic hardship, except method of leaving (where those leaving due to medical or unplanned discharge were more likely to encounter most forms of hardship as veterans), and rank which is itself related to socioeconomic status. CONCLUSION: Transition and resettlement provisions become increasingly generous with longer service, yet this paper shows the need for those services becomes progressively less necessary as personnel acquire seniority and skills, and instead could be best targeted at unplanned leavers, taking socioeconomic status into consideration. Many will agree that longer service should be more rewarded, but the opposite is true if provision instead reflects need rather than length of service. This is a social, political and ethical dilemma.

Asunto(s)

Personal Militar , Trastornos por Estrés Postraumático , Veteranos , Estudios de Cohortes , Humanos , Salud Mental , Prevalencia , Clase Social , Trastornos por Estrés Postraumático/epidemiología , Reino Unido/epidemiología

RESUMEN

The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The Ki values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH- influences the formation of the covalent adduct essential for effective inactivation of MAO.

Asunto(s)

Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/química , Sitios de Unión , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Oxidación-Reducción , Unión Proteica , Relación Estructura-Actividad , Especificidad por Sustrato , Factores de Tiempo

RESUMEN

A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide (5a-5h) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring (12a-12d) decreased inhibition, but a less flexible linker (14a-14d) resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.

RESUMEN

Mitochondrial dysfunction has a recognised role in the progression of Alzheimer's disease (AD) pathophysiology. Cerebral perfusion becomes increasingly inefficient throughout ageing, leading to unbalanced mitochondrial dynamics. This effect is exaggerated by amyloid ß (Aß) and phosphorylated tau, two hallmark proteins of AD pathology. A neuroprotective role for the adipose-derived hormone, leptin, has been demonstrated in neuronal cells. However, its effects with relation to mitochondrial function in AD remain largely unknown. To address this question, we have used both a glucose-serum-deprived (CGSD) model of ischaemic stroke in SH-SY5Y cells and a Aß1-42 -treatment model of AD in differentiated hippocampal cells. Using a combination of 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) and MitoRed staining techniques, we show that leptin prevents depolarisation of the mitochondrial membrane and excessive mitochondrial fragmentation induced by both CGSD and Aß1-42 . Thereafter, we used ELISAs and a number of activity assays to reveal the biochemical underpinnings of these processes. Specifically, leptin was seen to inhibit up-regulation of the mitochondrial fission protein Fis1 and down-regulation of the mitochondrial fusion protein, Mfn2. Furthermore, leptin was seen to up-regulate the expression and activity of the antioxidant enzyme, monoamine oxidase B. Herein we provide the first demonstration that leptin is sufficient to protect against aberrant mitochondrial dynamics and resulting loss of function induced by both CGSD and Aß1-42 . We conclude that the established neuroprotective actions of leptin may be facilitated through regulation of mitochondrial dynamics.

Asunto(s)

Leptina/farmacología , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Dinámicas Mitocondriales/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Péptidos beta-Amiloides/farmacología , Animales , Línea Celular , GTP Fosfohidrolasas/antagonistas & inhibidores , GTP Fosfohidrolasas/biosíntesis , Glucosa/deficiencia , Hipocampo/citología , Hipocampo/patología , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Ratones , Mitocondrias/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/biosíntesis , Monoaminooxidasa/metabolismo , Fragmentos de Péptidos/farmacología , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

BACKGROUND: Drinking motivations within the UK military have not been studied despite the high prevalence of alcohol misuse in this group. AIMS: We aimed to characterize drinking motivations and their demographic, military and mental health associations in UK serving and ex-serving personnel. METHODS: Serving and ex-serving personnel reporting mental health, stress or emotional problems occurring in the last 3 years were selected from an existing cohort study. A semi-structured telephone interview survey examined participants' mental health, help-seeking, alcohol use and drinking motivations. RESULTS: Exploratory factor analysis of drinking motivations in military personnel (n = 1279; response rate = 84.6%) yielded 2 factors, labelled 'drinking to cope' and 'social pressure'. Higher drinking to cope motivations were associated with probable anxiety (rate ratio [RR] = 1.4; 95% confidence interval [CI] = 1.3-1.5), depression (RR = 1.3; 95% CI = 1.2-1.4) and post-traumatic stress disorder (RR = 1.4; 95% CI = 1.3-1.6). Higher social pressure motivations were associated with probable anxiety (odds ratio = 1.1; 95% CI = 1.0-1.1). Alcohol misuse and binge drinking were associated with reporting higher drinking to cope motivations, drinking at home and drinking alone. CONCLUSIONS: Amongst military personnel with a stress, emotional or mental health problem, those who drink to cope with mental disorder symptoms or because of social pressure, in addition to those who drink at home or drink alone, are more likely to also drink excessively.

Asunto(s)

Consumo de Bebidas Alcohólicas/psicología , Ansiedad/psicología , Personal Militar/psicología , Motivación , Enfermedades Profesionales/psicología , Adaptación Psicológica , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Alcoholismo/epidemiología , Alcoholismo/psicología , Ansiedad/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/epidemiología , Oportunidad Relativa , Prevalencia , Encuestas y Cuestionarios , Reino Unido/epidemiología , Adulto Joven

RESUMEN

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aß anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 µM), MAO B (0.26 µM), and AChE (52 µM), while 32 exhibited a lead for selective MAO A (0.12 µM) inhibition coupled to AChE (48 µM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aß1-42 , was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aß1-42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 µM), making it a potential lead for Alzheimer's disease application.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Nitrilos/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Biología Computacional/métodos , Simulación por Computador , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Nitrilos/química , Nitrilos/farmacología , Relación Estructura-Actividad

RESUMEN

Successful propargylamine drugs such as deprenyl inactivate monoamine oxidase (MAO), a target in multi-faceted approaches to prevent neurodegeneration in the aging population, but the chemical structure and mechanism of the irreversible inhibition are still debated. We characterized the covalent cyanine structure linking the multi-target propargylamine inhibitor ASS234 and the flavin adenine dinucleotide in MAO-A using a combination of ultra-high performance liquid chromatography, spectroscopy, mass spectrometry, and computational methods. The partial double bond character of the cyanine chain gives rise to 4 interconverting geometric isomers of the adduct which were chromatographically separated at low temperatures. The configuration of the cyanine linker governs adduct stability with segments of much higher flexibility and rigidity than previously hypothesized. The findings indicate the importance of intramolecular electrostatic interactions in the MAO binding site and provide key information relevant to incorporation of the propargyl moiety into novel multi-target drugs. Based on the structure, we propose a mechanism of MAO inactivation applicable to all propargylamine inhibitors.

RESUMEN

Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism, and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modelling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation. However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine, and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration.

Asunto(s)

Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Diseño de Fármacos , Humanos

RESUMEN

Diseases of infection, of neurodegeneration (such as Alzheimer's and Parkinson's diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.

RESUMEN

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Asunto(s)

Antioxidantes/química , Inhibidores de la Colinesterasa/química , Antagonistas de los Receptores Histamínicos H3/química , Indoles/química , Inhibidores de la Monoaminooxidasa/química , Fármacos Neuroprotectores/química , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Barrera Hematoencefálica/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/uso terapéutico , Ligandos , Ratones , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacocinética , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/uso terapéutico , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapéutico

RESUMEN

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Asunto(s)

Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Descubrimiento de Drogas , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Animales , Inhibidores de la Colinesterasa/uso terapéutico , Colinesterasas/química , Colinesterasas/metabolismo , Simulación por Computador , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Humanos , Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neurotransmisores/antagonistas & inhibidores , Neurotransmisores/metabolismo , Relación Estructura-Actividad

RESUMEN

INTRODUCTION: There are higher levels of alcohol misuse in the military compared to the general population. Yet there is a dearth of research in military populations on the longitudinal patterns of alcohol use. This study aims to identify group trajectories of alcohol consumption in the UK military and to identify associations with childhood adversity, deployment history and mental disorder. METHODS: Data on weekly alcohol consumption across an eight year period and three phases of a UK military cohort study (n=667) were examined using growth mixture modelling. RESULTS: Five alcohol trajectory classes were identified: mid-average drinkers (55%), abstainers (4%), low level drinkers (19%), decreasing drinkers (3%) and heavy drinkers (19%). Alcohol consumption remained stable over the three periods in all classes, other than in the small decreasing trajectory class. Individuals in the heavy drinking class were more likely to have deployed to Iraq. Abstainers and heavy drinkers were more likely to report post-traumatic stress disorders at baseline compared to average drinkers. CONCLUSIONS: Heavy drinkers in the UK military did not change their drinking pattern over a period of eight years. This highlights the need to develop effective preventive programmes to lessen the physical and psychological consequences of long-term heavy alcohol use. Individuals with a mental health problem appeared more likely to either be drinking at a high level or to be abstaining from use.

Asunto(s)

Abstinencia de Alcohol/estadística & datos numéricos , Consumo de Bebidas Alcohólicas/epidemiología , Alcoholismo/epidemiología , Salud Mental , Personal Militar , Trastornos por Estrés Postraumático/epidemiología , Adulto , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Reino Unido

RESUMEN

BACKGROUND: Rates of hazardous and harm-related drinking are higher in the military and veteran populations compared to the general population. Brief alcohol interventions (BAIs) targeting alcohol use appear to reduce harmful drinking in the general population. However, less is known about the efficacy of BAIs targeting alcohol in military and veteran populations. METHODS: A systematic review and meta-analysis was conducted to assess the type and efficacy of BAIs used to reduce alcohol use in military and veteran populations conducted from 2000 onwards. The meta-analysis was conducted using a standardised outcome measure of change in average weekly drinks (AWDs) from baseline to follow-up. RESULTS: The search revealed 10 papers that met the search criteria, and that reported data on 11 interventions included in the systematic review. 8 papers (reporting on 9 different interventions) were included in the meta-analysis after 2 papers were excluded for which the relevant outcome data were not available. There was no overall effect of BAIs; a non-significant weekly drink reduction of 0.95 drinks was found (95% CI, -0.17 to 2.07). This lack of efficacy persisted regardless of military group (conscripts, serving or veterans) and method of delivery (i.e., face-to-face, web-based or written information). Furthermore, sensitivity analyses revealed this small drink reduction was driven mainly by a single study. CONCLUSIONS: Based on these findings, existing BAIs do not seem to be efficacious in reducing alcohol use in military populations, despite some encouraging results from one electronic intervention which was of extensive duration.

Asunto(s)

Consumo de Bebidas Alcohólicas , Alcoholismo/rehabilitación , Personal Militar/estadística & datos numéricos , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/prevención & control , Consejo , Etanol/química , Humanos , Veteranos

Asunto(s)

Monoaminas Biogénicas/metabolismo , Sistema Nervioso/efectos de los fármacos , Sistema Nervioso/metabolismo , Neurotransmisores/farmacología , Animales , Humanos , Neurotransmisores/uso terapéutico

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aß). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34µM and 0.30µM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.

Asunto(s)

3-Hidroxiacil-CoA Deshidrogenasas/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Benzotiazoles/farmacología , Inhibidores Enzimáticos/farmacología , Monoaminooxidasa/metabolismo , Compuestos de Fenilurea/farmacología , Tiourea/farmacología , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Enfermedad de Alzheimer/metabolismo , Benzotiazoles/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Compuestos de Fenilurea/química , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/química

RESUMEN

The regulation of brain monoamine levels is paramount for cognitive functions, and the monoamine oxidase (MAO A and B) enzymes play a central role in these processes. The aim of this study was to evaluate whether the procognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) are related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region-specific alterations in monoamine metabolism that differ from both of the classic MAO A and MAO B inhibitors, clorgyline and l-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramine. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat but not human microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistent with the poor affinity of F2MPA for MAO.

Asunto(s)

Corteza Cerebral/efectos de los fármacos , Furanos/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Norepinefrina/metabolismo , Serotonina/metabolismo , Animales , Corteza Cerebral/metabolismo , Clorgilina/farmacología , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Selegilina/farmacología

RESUMEN

HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases. Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to "dirty drugs" for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent metabolism of MTDLs.