Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson's disease.
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.
Petzer
Jacobus P
JP
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, 2520, South Africa. jacques.petzer@nwu.ac.za
Castagnoli
Neal
N
Schwarzschild
Michael A
MA
Chen
Jiang-Fan
JF
Van der Schyf
Cornelis J
CJ
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002490:Central Nervous System / Q000201:enzymology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004359:Drug Therapy, Combination; D020820:Dyskinesias / Q000188:drug therapy; D000882:Haplorhini; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D014970:Xanthines / Q000627:therapeutic use
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D043683:Receptors, Adenosine A2; D014970:Xanthines; C008514:methylxanthine; D007980:Levodopa; D008995:Monoamine Oxidase; D004298:Dopamine