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Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists.
Bioorg Med Chem. 2003 Apr 03; 11(7):1299-310.BM

Abstract

Adenosine receptor antagonists that are selective for the A(2A) receptor subtype (A(2A) antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A(2A) antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A(2A) antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A(2A) antagonists examined display significant MAO-B inhibitory properties in vitro with K(i) values in the low micro M to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A(2A) antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A(2A) receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD.

Authors+Show Affiliations

Petzer JP
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061-0212, USA.
Steyn S
No affiliation info available
Castagnoli KP
No affiliation info available
Chen JF
No affiliation info available
Schwarzschild MA
No affiliation info available
Van der Schyf CJ
No affiliation info available
Castagnoli N
No affiliation info available

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAnimalsAntiparkinson AgentsBenzimidazolesDopamine AgentsHumansIn Vitro TechniquesIndicators and ReagentsKineticsMiceMice, Inbred C57BLMitochondria, LiverMonoamine OxidaseMonoamine Oxidase InhibitorsNeuroprotective AgentsOxidopaminePapioParkinson Disease, SecondaryPhotochemistryPurinergic P1 Receptor AntagonistsPurinesReceptor, Adenosine A2AStereoisomerismStructure-Activity RelationshipSympatholyticsXanthines

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12628657

Citation

Petzer, Jacobus P., et al. "Inhibition of Monoamine Oxidase B By Selective Adenosine A2A Receptor Antagonists." Bioorganic & Medicinal Chemistry, vol. 11, no. 7, 2003, pp. 1299-310.
Petzer JP, Steyn S, Castagnoli KP, et al. Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorg Med Chem. 2003;11(7):1299-310.
Petzer, J. P., Steyn, S., Castagnoli, K. P., Chen, J. F., Schwarzschild, M. A., Van der Schyf, C. J., & Castagnoli, N. (2003). Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorganic & Medicinal Chemistry, 11(7), 1299-310.
Petzer JP, et al. Inhibition of Monoamine Oxidase B By Selective Adenosine A2A Receptor Antagonists. Bioorg Med Chem. 2003 Apr 3;11(7):1299-310. PubMed PMID: 12628657.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. AU - Petzer,Jacobus P, AU - Steyn,Salome, AU - Castagnoli,Kay P, AU - Chen,Jiang Fan, AU - Schwarzschild,Michael A, AU - Van der Schyf,Cornelis J, AU - Castagnoli,Neal, PY - 2003/3/12/pubmed PY - 2003/11/11/medline PY - 2003/3/12/entrez SP - 1299 EP - 310 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 11 IS - 7 N2 - Adenosine receptor antagonists that are selective for the A(2A) receptor subtype (A(2A) antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A(2A) antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A(2A) antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A(2A) antagonists examined display significant MAO-B inhibitory properties in vitro with K(i) values in the low micro M to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A(2A) antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A(2A) receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/12628657/Inhibition_of_monoamine_oxidase_B_by_selective_adenosine_A2A_receptor_antagonists_ DB - PRIME DP - Unbound Medicine ER -