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ACS Chemical Neuroscience Dec 2023The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the... (Review)
Review
The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the antidepressant. In the years and decades that followed, MAOIs have been used in the treatment of several pathologies including Parkinson's disease, Alzheimer's disease, and various cancers and as anti-inflammatory agents. Despite once enjoying widespread use, MAOIs have dwindled in popularity due to side effects, food-drug interactions, and the introduction of other antidepressant drug classes such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The recently published prescriber's guide for the use of MAOIs in treating depression has kindled a resurgence of their use in the clinical space. It is therefore timely to review key aspects of the four "classic" MAOIs: high-dose selegiline, isocarboxazid, phenelzine, and tranylcypromine. This review discusses their chemical synthesis, metabolism, pharmacology, adverse effects, and the history and importance of these drugs within the broader field of chemical neuroscience.
Topics: Tranylcypromine; Phenelzine; Isocarboxazid; Selegiline; Antidepressive Agents; Monoamine Oxidase Inhibitors
PubMed: 37966854
DOI: 10.1021/acschemneuro.3c00591 -
Chemical Biology & Drug Design Mar 2020Monoamine oxidase (MAO) is an important drug target as the MAO isoforms play key roles in neurodegenerative disorders such as Alzheimer's disease and Parkinson's...
Monoamine oxidase (MAO) is an important drug target as the MAO isoforms play key roles in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as in neuropsychiatric diseases such as depression. Methylene blue is an inhibitor of MAO-A, while azure B, the major metabolite of methylene blue, and various other structural analogues retain the ability to inhibit MAO-A. Based on this, the present study evaluated 22 dyes, many of which are structurally related to methylene blue, as potential inhibitors of human MAO-A and MAO-B. The results highlighted three dye compounds as good potency competitive and reversible MAO inhibitors, and which exhibit higher MAO inhibition than methylene blue: acridine orange, oxazine 170 and Darrow red. Acridine orange was found to be a MAO-A specific inhibitor (IC = 0.017 μM), whereas oxazine 170 is a MAO-B specific inhibitor (IC = 0.0065 μM). Darrow red was found to be a non-specific MAO inhibitor (MAO-A, IC = 0.059 μM; MAO-B, IC = 0.065 μM). These compounds may be advanced for further testing and preclinical development, or be used as possible lead compounds for the future design of MAO inhibitors.
Topics: Acridine Orange; Anthraquinones; Azure Stains; Coloring Agents; Drug Design; Humans; Methylene Blue; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Oxazines; Structure-Activity Relationship
PubMed: 31834986
DOI: 10.1111/cbdd.13654 -
Combinatorial Chemistry & High... 2017Background Due to the limited number of MAO inhibitors in the clinics, several research efforts are aimed at the discovery of novel MAO inhibitors. At present, a high... (Review)
Review
UNLABELLED
Background Due to the limited number of MAO inhibitors in the clinics, several research efforts are aimed at the discovery of novel MAO inhibitors. At present, a high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action of drug.
AIM
Most of the existing MAO inhibitors lead to side effects due to the lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B. Selective inhibition of MAO-A results in the elevated level of serotonin and noradrenaline. Hence, MAO-A inhibitors can be used for improving the symptoms of depression. The selective MAO-B inhibitors are used with L-DOPA and/or dopamine agonists in the symptomatic treatment of Parkinson's disease. The present study was aimed to describe the recently developed hits of MAO inhibitors.
METHOD
At present, CADD techniques are gaining an attention in rationale drug discovery of MAO inhibitors, and several research groups employed CADD approaches on various chemical scaffolds to identify novel MAO inhibitors. These computational techniques assisted in the development of lead molecules with improved pharmacodynamics / pharmacokinetic properties toward MAOs. Further, CADD techniques provided a better understanding of structural aspects of molecular targets and lead molecules.
CONCLUSIONS
The present review describes the importance of structural features of potential chemical scaffolds as well as the role of computational approaches like ligand docking, molecular dynamics, QSAR and pharmacophore modeling in the development of novel MAO inhibitors.
Topics: Dose-Response Relationship, Drug; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Structure-Activity Relationship
PubMed: 28294055
DOI: 10.2174/1386207320666170310121337 -
Central Nervous System Agents in... 2016Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of... (Review)
Review
INTRODUCTION
Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of pharmacological actions.
DISCUSSION
The present review focused our attention onto the monoamine oxidase inhibitory activity of natural and synthetic chalcones. The review also emphasises the structure-activity relationship studies and molecular recognition of chalcones towards MAO-A and B inhibition.
CONCLUSION
Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors.
Topics: Animals; Chalcones; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 26429556
DOI: 10.2174/1871524915666151002124443 -
Journal of Neural Transmission (Vienna,... Jun 2022Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and... (Review)
Review
Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly.
Topics: Antiparkinson Agents; Dopamine Agents; Humans; Indans; Levodopa; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline
PubMed: 35107654
DOI: 10.1007/s00702-022-02465-w -
Journal of Neural Transmission (Vienna,... Nov 2018Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Two pharmacological types with different substrate and... (Review)
Review
Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Two pharmacological types with different substrate and inhibitor specificities were reported. Molecular cloning revealed that the two types of MAO were different genes expressed as different proteins with different functions. MAO A and B have identical intron-exon organization derived by duplication of a common ancestral gene thus they are termed isoenzymes. MAO A knockout mice exhibited aggression, the first clear evidence linking genes to behavior. MAO A KO mice exhibited autistic-like behaviors which could be prevented by reducing serotonin levels at an early developmental age (P1-P7) providing potential therapy. MAO B KO mice were non-aggressive and resistant to Parkinsongenic neurotoxin. More recently it was found that MAO A is overexpressed in prostate cancer and correlates with degree of malignancy. The oncogenic mechanism involves a ROS-activated AKT/FOXO1/TWIST1 signaling pathway. Deletion of MAO A reduced prostate cancer stem cells and suppressed invasive adenocarcinoma. MAO A was also overexpressed in classical Hodgkin lymphoma and glioma brain tumors. MAO B was overexpressed in glioma and non-small cell lung cancer. MAO A inhibitors reduce the growth of prostate cancer, drug sensitive and resistant gliomas and classical Hodgkin lymphoma, and enhance standard chemotherapy. Currently, we are developing NIR dye-conjugated clorgyline (MAO A inhibitor) as a novel dual therapeutic/diagnostic agent for cancer. A phase II clinical trial of MAO inhibitor for biochemical recurrent prostate cancer is ongoing. The role of MAO A and B in several cancer types opens new avenues for cancer therapies.
Topics: Animals; Antineoplastic Agents; Behavior; Humans; Isoenzymes; Monoamine Oxidase; Monoamine Oxidase Inhibitors
PubMed: 30259128
DOI: 10.1007/s00702-018-1927-8 -
Reviews in Medical Virology Sep 2023Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems... (Review)
Review
Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein-Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M-30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases.
Topics: Humans; Monoamine Oxidase; Epstein-Barr Virus Infections; COVID-19; Herpesvirus 4, Human; Monoamine Oxidase Inhibitors
PubMed: 37294534
DOI: 10.1002/rmv.2465 -
ChemMedChem Aug 2020Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin- and heme-dependent enzymes, and is often used as an NADPH oxidase inhibitor. We...
Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin- and heme-dependent enzymes, and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well-known drug targets, the human monoamine oxidases MAO A and B. UV-visible spectrophotometry and steady-state kinetics experiments demonstrate that DPI acts as a competitive and reversible MAO inhibitor with K values of 1.7 and 0.3 μM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active-site cavity to establish multiple hydrophobic interactions with the surrounding side chains and the flavin. These data prove that DPI is a genuine MAO inhibitor and that the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against the MAOs, two major reactive oxygen species (ROS)-producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.
Topics: Dose-Response Relationship, Drug; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Onium Compounds; Structure-Activity Relationship
PubMed: 32459875
DOI: 10.1002/cmdc.202000264 -
Metabolic Brain Disease Oct 2017Methylene Blue (MB) is considered to have diverse medical applications and is a well-described treatment for methemoglobinemias and ifosfamide-induced encephalopathy. In... (Review)
Review
Methylene Blue (MB) is considered to have diverse medical applications and is a well-described treatment for methemoglobinemias and ifosfamide-induced encephalopathy. In recent years the focus has shifted to MB as an antimalarial agent and as a potential treatment for neurodegenerative disorders such as Alzheimer's disease. Of interest are reports that MB possesses antidepressant and anxiolytic activity in pre-clinical models and has shown promise in clinical trials for schizophrenia and bipolar disorder. MB is a noteworthy inhibitor of monoamine oxidase A (MAO-A), which is a well-established target for antidepressant action. MB is also recognized as a non-selective inhibitor of nitric oxide synthase (NOS) and guanylate cyclase. Dysfunction of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is strongly linked to the neurobiology of mood, anxiety and psychosis, while the inhibition of NOS and/or guanylate cyclase has been associated with an antidepressant response. This action of MB may contribute significantly to its psychotropic activity. However, these disorders are also characterised by mitochondrial dysfunction and redox imbalance. By acting as an alternative electron acceptor/donor MB restores mitochondrial function, improves neuronal energy production and inhibits the formation of superoxide, effects that also may contribute to its therapeutic activity. Using MB in depression co-morbid with neurodegenerative disorders, like Alzheimer's and Parkinson's disease, also represents a particularly relevant strategy. By considering their physicochemical and pharmacokinetic properties, analogues of MB may provide therapeutic potential as novel multi-target strategies in the treatment of depression. In addition, low MAO-A active analogues may provide equal or improved response with a lower risk of adverse effects.
Topics: Animals; Antidepressive Agents; Humans; Methylene Blue; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nitric Oxide Synthase
PubMed: 28762173
DOI: 10.1007/s11011-017-0081-6 -
Expert Opinion on Therapeutic Patents Mar 2018Monoamine oxidase (MAO) inhibitors, after the initial 'golden age', are currently used as third-line antidepressants (selective MAO-A inhibitors) or clinically enrolled... (Review)
Review
INTRODUCTION
Monoamine oxidase (MAO) inhibitors, after the initial 'golden age', are currently used as third-line antidepressants (selective MAO-A inhibitors) or clinically enrolled as co-adjuvants for neurodegenerative diseases (selective MAO-B inhibitors). However, the research within this field is always increasing due to their pivotal role in modulating synaptic functions and monoamines metabolism.
AREAS COVERED
In this paper, MAO inhibitors (2015-2017) are disclosed ordering all the patents according to their chemical scaffold. Structure-activity relationships (SARs) are extrapolated for the most investigated chemotypes (coumarins, pyrazole/oxazepinones, (hetero)arylamides). 108 Compounds are divided into two main groups: newly synthesized molecules and naturally-occurring metabolites. Finally, new therapeutic options are outlined to ensure a more complete view on the potential of these inhibitors.
EXPERT OPINION
New proposed MAO inhibitors are endowed with a marked isoform selectivity, with innovative therapeutic potential toward other targets (gliomas, inflammation, muscle dystrophies, migraine, chronic pain, pseudobulbar affect), and with a promising ability to address multi-faceted pathologies such as Alzheimer's disease. The increasing number of patents is analyzed collecting data from 2002 to 2017.
Topics: Animals; Antidepressive Agents; Drug Design; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Patents as Topic; Structure-Activity Relationship
PubMed: 29324067
DOI: 10.1080/13543776.2018.1427735