Dual Targeting of Adenosine A2A Receptors and Monoamine Oxidase B by 4H-3,1-Benzothiazin-4-ones

Blockade of A(2A) adenosine receptors (A(2A)ARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A(2A)ARs (K-i human A(2A)AR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A(2A)AR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, K-i human A(2A), 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A(2A)AR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A(2A)AR/MAO-B dual target approach in PD.