Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Abstract

Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

Design of enamides as new selective monoamine oxidase-B inhibitors

“…[ 4 ] Furthermore, considerations of the importance of monoaminergic signalling in the biogenic amine deficiencies indicate that MAOs could be involved in the regulation of mood and cognitive function. [ 5 ] Based on knowledge of the homology and catalytic mechanisms of MAO‐A and B, several research groups have focused on the design and development of selective MAO inhibitors, and available evidence indicates MAO‐A and MAO‐B are important drug targets for the treatment of neuropsychiatric and neurodegenerative disorders like anxiety, depression, Alzheimer's disease (AD) and Parkinson's disease (PD). [ 6 ] Oxidative deamination by MAO‐B usually generates ammonia, hydrogen peroxide and various aldehydes as by‐products.…”

“…The HBA or HBD groups may be present in the linker, which can connect with hydrophobic nucleus or hydrophobic zone of the inhibitors. [ 5,37 ] We considered that the presence of the two hydrophobic pharmacophoric features linked with an amide‐connected olefinic spacer in enamides would result in recognition by the inhibitor binding cavity of MAO‐B. Recently, some amides have been reported to exhibit potent selective MAO‐B inhibitory activity.…”

Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

“…The molecules with reversible selective inhibition of MAO-A or MAO-B have therapeutic potential for the treatment of neurological and psychiatric disorders, especially caused due to depletion of neurotransmitter biogenic amines [9,29,30]. Previous studies from our lab have reported selective inhibition of human MAO-B with flavonoid natural products [18][19][20].…”

Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease

“…On the other hand, there is still a pressing medical need for the development of reversible selective MAO-B inhibitors with effectiveness and safety for long-term use to treat PD [ 112 ]. Selegiline and rasagiline are irreversible MAO-B inhibitors with undesirable adverse effects, including hallucination and headache, the production of neurotoxic or ineffective metabolites, and gradual short-lived action after long-term use.…”