Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists.
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.
Petzer
Jacobus P
JP
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061-0212, USA.
Steyn
Salome
S
Castagnoli
Kay P
KP
Chen
Jiang Fan
JF
Schwarzschild
Michael A
MA
Van der Schyf
Cornelis J
CJ
Castagnoli
Neal
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D015259:Dopamine Agents; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine; D010215:Papio; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D010777:Photochemistry; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013565:Sympatholytics; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology*
D000978:Antiparkinson Agents; D001562:Benzimidazoles; D015259:Dopamine Agents; D007202:Indicators and Reagents; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; D013565:Sympatholytics; D014970:Xanthines; C111599:istradefylline; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase