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Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson's disease.
Neurotherapeutics. 2009 Jan; 6(1):141-51.N

Abstract

Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A(2A) receptor is one such target. Antagonists of this receptor (A(2A) antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A(2A) antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A(2A) antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A(2A) receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Authors+Show Affiliations

Petzer JP
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, 2520, South Africa. jacques.petzer@nwu.ac.za
Castagnoli N
No affiliation info available
Schwarzschild MA
No affiliation info available
Chen JF
No affiliation info available
Van der Schyf CJ
No affiliation info available

MeSH

Adenosine A2 Receptor AntagonistsAnimalsAntiparkinson AgentsCentral Nervous SystemDopamineDrug Therapy, CombinationDyskinesiasHaplorhiniHumansLevodopaMonoamine OxidaseMonoamine Oxidase InhibitorsNeuroprotective AgentsParkinson DiseaseReceptors, Adenosine A2Xanthines

Pub Type(s)

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

Language

eng

PubMed ID

19110205

Citation

Petzer, Jacobus P., et al. "Dual-target-directed Drugs That Block Monoamine Oxidase B and Adenosine A(2A) Receptors for Parkinson's Disease." Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics, vol. 6, no. 1, 2009, pp. 141-51.
Petzer JP, Castagnoli N, Schwarzschild MA, et al. Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson's disease. Neurotherapeutics. 2009;6(1):141-51.
Petzer, J. P., Castagnoli, N., Schwarzschild, M. A., Chen, J. F., & Van der Schyf, C. J. (2009). Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson's disease. Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics, 6(1), 141-51. https://doi.org/10.1016/j.nurt.2008.10.035
Petzer JP, et al. Dual-target-directed Drugs That Block Monoamine Oxidase B and Adenosine A(2A) Receptors for Parkinson's Disease. Neurotherapeutics. 2009;6(1):141-51. PubMed PMID: 19110205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson's disease. AU - Petzer,Jacobus P, AU - Castagnoli,Neal,Jr AU - Schwarzschild,Michael A, AU - Chen,Jiang-Fan, AU - Van der Schyf,Cornelis J, PY - 2008/12/27/entrez PY - 2008/12/27/pubmed PY - 2009/4/3/medline SP - 141 EP - 51 JF - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics JO - Neurotherapeutics VL - 6 IS - 1 N2 - Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A(2A) receptor is one such target. Antagonists of this receptor (A(2A) antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A(2A) antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A(2A) antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A(2A) receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound. SN - 1933-7213 UR - https://www.unboundmedicine.com/medline/citation/19110205/Dual_target_directed_drugs_that_block_monoamine_oxidase_B_and_adenosine_A_2A__receptors_for_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1933-7213(08)00232-8 DB - PRIME DP - Unbound Medicine ER -