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Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones.
J Med Chem. 2013 Jun 13; 56(11):4580-96.JM

Abstract

Blockade of A2A adenosine receptors (A2AARs) 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 A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/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, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Stössel A
PharmaCenter Bonn, University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany.
Schlenk M
No affiliation info available
Hinz S
No affiliation info available
Küppers P
No affiliation info available
Heer J
No affiliation info available
Gütschow M
No affiliation info available
Müller CE
No affiliation info available

MeSH

Adenosine A2 Receptor AntagonistsAnimalsBenzothiadiazinesBrainCHO CellsCricetinaeCricetulusCyclic AMPHumansIn Vitro TechniquesIsoenzymesLiverMonoamine OxidaseMonoamine Oxidase InhibitorsPhenylbutyratesRadioligand AssayRatsRats, Sprague-DawleyReceptor, Adenosine A2AStereoisomerismStructure-Activity RelationshipThiazines

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23631427

Citation

Stössel, Anne, et al. "Dual Targeting of Adenosine A(2A) Receptors and Monoamine Oxidase B By 4H-3,1-benzothiazin-4-ones." Journal of Medicinal Chemistry, vol. 56, no. 11, 2013, pp. 4580-96.
Stössel A, Schlenk M, Hinz S, et al. Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones. J Med Chem. 2013;56(11):4580-96.
Stössel, A., Schlenk, M., Hinz, S., Küppers, P., Heer, J., Gütschow, M., & Müller, C. E. (2013). Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones. Journal of Medicinal Chemistry, 56(11), 4580-96. https://doi.org/10.1021/jm400336x
Stössel A, et al. Dual Targeting of Adenosine A(2A) Receptors and Monoamine Oxidase B By 4H-3,1-benzothiazin-4-ones. J Med Chem. 2013 Jun 13;56(11):4580-96. PubMed PMID: 23631427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones. AU - Stössel,Anne, AU - Schlenk,Miriam, AU - Hinz,Sonja, AU - Küppers,Petra, AU - Heer,Jag, AU - Gütschow,Michael, AU - Müller,Christa E, Y1 - 2013/05/30/ PY - 2013/5/2/entrez PY - 2013/5/2/pubmed PY - 2013/8/21/medline SP - 4580 EP - 96 JF - Journal of medicinal chemistry JO - J Med Chem VL - 56 IS - 11 N2 - Blockade of A2A adenosine receptors (A2AARs) 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 A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/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, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/23631427/Dual_targeting_of_adenosine_A_2A__receptors_and_monoamine_oxidase_B_by_4H_31_benzothiazin_4_ones_ L2 - https://doi.org/10.1021/jm400336x DB - PRIME DP - Unbound Medicine ER -