Broad spectrum anticonvulsant activity of BW534U87: possible role of an adenosine-dependent mechanism.
The novel putative anticonvulsant drug 1-[2,6-difluorophenyl)-methyl]-1H-1,2,3-triazolo[4,5-c]) pyridine-4-amine monohydrochloride (BW534U87) effectively reduced seizures induced in rodents by threshold maximal and supramaximal electroshock, electrical kindling, pentylenetetrazole (PTZ) infusion and by vestibular stimulation in the genetically seizure-prone epilepsy-like (EL) mouse. The range of animal seizure models in which BW534U87 was effective is consistent with a broad spectrum anticonvulsant profile. In the EL mouse, the activity of BW534U87 was partially reversed by predosing with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), suggesting that an adenosine-dependent mechanism contributed to the antiseizure activity of the drug. BW534U87 inhibited rat brain homogenate adenosine deaminase activity, thus, raising the possibility that, by blocking the metabolism of endogenous adenosine by this route, BW534U87 limited seizure activity by promoting the inhibitory tone mediated by endogenous adenosine in the brain. The seizure protection conferred by the selective adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) in EL mice and mice infused with PTZ confirms that inhibition of adenosine metabolism by deamination is an effective antiseizure strategy in these models.
Southam
Eric
E
GlaxoSmithKline, New Frontiers Science Park, Essex CM195AW, Harlow, UK. es36365@gsk.com
Stratton
Sharon C
SC
Sargent
Rebecca S
RS
Brackenborough
Kim T
KT
Duffy
Claire
C
Hagan
Russell M
RM
Pratt
Gerard D
GD
Jones
Stacey A
SA
Morgan
Philip F
PF
D000225:Adenine / Q000031:analogs & derivatives*; D000241:Adenosine / Q000502:physiology*; D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D014230:Triazoles / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D000927:Anticonvulsants; D003292:Convulsants; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D014230:Triazoles; D014970:Xanthines; C010192:9-(2-hydroxy-3-nonyl)adenine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine; C096008:BW 534U87; D010433:Pentylenetetrazole