Review of β‐carboline and its derivatives as selective MAO‐A inhibitors

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Abstract

As flavin adenine dinucleotide (FAD)‐dependent enzymes, monoamine oxidases (MAOs) catalyze the oxidative deamination of various endogenous and exogenous amines. MAO‐A inhibitors are thought to be effective therapeutic agents for treating neurological diseases including depression and anxiety. Due to the academic challenge of developing new human (h) MAO‐A inhibitors and the potential for discovering substances with remarkable properties compared to existing MAO‐A inhibitors, numerous research groups are looking into novel classes of chemical compounds that may function as selective hMAO‐A inhibitors. β‐Carbolines are reported to be a prominent class of bioactive molecules exhibiting MAO‐A inhibition. Chemically, β‐carboline is a tricyclic pyrido‐3,4‐indole ring. It has only recently been discovered that this chemotype has highly effective and specific MAO‐A inhibitory activity. In this review, structure–activity relationship studies included in particular research publications from the 1960s to the present are discussed with regard to β‐carboline and its analogs. This comprehensive information helps to design and develop a new family of MAO‐A inhibitors for the management of depressive disorders.

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The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).

Ronald C Kessler, Patricia Berglund, Olga Demler … (2003)

Uncertainties exist about prevalence and correlates of major depressive disorder (MDD). To present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on study patterns and correlates of treatment and treatment adequacy from the recently completed National Comorbidity Survey Replication (NCS-R). Face-to-face household survey conducted from February 2001 to December 2002. The 48 contiguous United States. Household residents ages 18 years or older (N = 9090) who responded to the NCS-R survey. Prevalence and correlates of MDD using the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disability assessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV. The prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases were independently classified as clinically significant using the QIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured by SDS was substantial as indicated by 59.3% of 12-month cases with severe or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases received health care treatment for MDD, treatment was adequate in only 41.9% (95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment were far less numerous than those of prevalence. Major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. While the recent increase in treatment is encouraging, inadequate treatment is a serious concern. Emphasis on screening and expansion of treatment needs to be accompanied by a parallel emphasis on treatment quality improvement.

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Monoamine oxidase inactivation: from pathophysiology to therapeutics.

Marco Bortolato, Kevin Chen, Jean C Shih (2015)

Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, beta-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson's disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders.