Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists.
The principal therapeutic agents used in the management of Parkinson's disease (PD) enhance nigrostriatal dopaminergic flux through either replenishment of depleted dopamine stores or the action of dopaminergic agonists. Adenosine A2A receptor antagonists (e.g., KW-6002) may provide symptomatic relief in PD and perhaps also may display neuroprotective properties based on studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of nigrostriatal neurodegeneration. A second class of compounds that is neuroprotective in the MPTP model comprises inhibitors of the outer mitochondrial flavoenzyme monoamine oxidase B (MAO B), one of the two forms of MAO that regulate levels of brain neurotransmitter substances, including dopamine. In this article, data are presented that document the overlapping A2A antagonist and MAO B inhibitory properties of several 2-styrylxanthinyl derivatives. A limited structure-activity analysis of these compounds and structurally related analogs is provided. The results raise the possibility that a single structure may offer the combined benefits of two pharmacologic strategies, each with symptomatic and potential neuroprotective benefits, for the management of PD.
Castagnoli
Neal
N
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0212, USA. ncastagn@vt.edu
Petzer
Jacobus P
JP
Steyn
Salome
S
Castagnoli
Kay
K
Chen
Jiang-Fan
JF
Schwarzschild
Michael A
MA
Van der Schyf
Cornelis J
CJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000187:drug effects* / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019636:Neurodegenerative Diseases / Q000139:chemically induced; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010215:Papio; D011687:Purines / Q000494:pharmacology; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011687:Purines; C111599:istradefylline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase