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. 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. 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.

Caffeine and more specific antagonists of the adenosine A_2A receptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A_2A antagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP⁺, we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP⁺ and of MPP⁺, suggesting that CSC blocks the conversion of MPTP to MPDP⁺ in vivo. In assessing the direct effects of CSC and A_2A receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with aK _i value of 100 nm, whereas caffeine and another relatively specific A_2A antagonist produced little or no inhibition. The A_2A receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A_2A receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A_2A receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A_2A receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.