Dual-Target-Directed Drugs that Block Monoamine Oxidase B and Adenosine A2A Receptors for Parkinson's Disease

被引:61
作者
Petzer, Jacobus P. [1 ]
Castagnoli, Neal, Jr. [2 ,3 ]
Schwarzschild, Michael A. [4 ]
Chen, Jiang-Fan [5 ]
Van der Schyf, Cornelis J. [6 ]
机构
[1] North West Univ, Sch Pharm, ZA-2520 Potchefstroom, South Africa
[2] Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA
[3] Edward Via Coll Osteopath Med, Blacksburg, VA 24061 USA
[4] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA
[5] Boston Univ, Sch Med, Dept Neurol, Mol Neuropharmacol Lab, Boston, MA 02118 USA
[6] Northeastern Ohio Univ Coll Med & Pharm, Dept Pharmaceut Sci, Rootstown, OH 44272 USA
基金
新加坡国家研究基金会;
关键词
Parkinson's disease; monoamine oxidase B; adenosine A(2A) receptor; dual-target-directed drug; caffeine; L-DOPA; HUMAN-BRAIN; MAO-B; DOPAMINERGIC NEUROTOXICITY; ANTAGONIST ISTRADEFYLLINE; MOTOR COMPLICATIONS; SUBSTANTIA-NIGRA; RAT MODEL; INHIBITION; CAFFEINE;
D O I
10.1016/j.nurt.2008.10.035
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:141 / 151
页数:11
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