Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy.
Adenosine levels increase at seizure foci as part of a postulated endogenous negative feedback mechanism that controls seizure activity through activation of A1 adenosine receptors. Agents that amplify this site- and event-specific surge of adenosine could provide antiseizure activity similar to that of adenosine receptor agonists but with fewer dose-limiting side effects. Inhibitors of adenosine kinase (AK) were examined because AK is normally the primary route of adenosine metabolism. The AK inhibitors 5'-amino-5'-deoxyadenosine, 5-iodotubercidin, and 5'-deoxy-5-iodotubercidin inhibited maximal electroshock (MES) seizures in rats. Several structural classes of novel AK inhibitors were identified and shown to exhibit similar activity, including a prototype inhibitor, 4-(N-phenylamino)-5-phenyl-7-(5'-deoxyribofuranosyl)pyrrolo[2, 3-d]pyrimidine (GP683; MES ED50 = 1.1 mg/kg). AK inhibitors also reduced epileptiform discharges induced by removal of Mg2+ in a rat neocortical preparation. Overall, inhibitors of adenosine deaminase or of adenosine transport were less effective. The antiseizure activities of GP683 in the in vivo and in vitro preparations were reversed by the adenosine receptor antagonists theophylline and 8-(p-sulfophenyl)theophylline. GP683 showed little or no hypotension or bradycardia and minimal hypothermic effect at anticonvulsant doses. This improved side effect profile contrasts markedly with the profound hypotension, bradycardia, and hypothermia and greater inhibition of motor function observed with the adenosine receptor agonist N6-cyclopentyladenosine and opens the way to clinical evaluation of AK inhibitors as a novel, adenosine-based approach to anticonvulsant therapy.
Wiesner
J B
JB
Metabasis Therapeutics, Inc., San Diego, California, USA. wiesner@mbasis.com
Ugarkar
B G
BG
Castellino
A J
AJ
Barankiewicz
J
J
Dumas
D P
DP
Gruber
H E
HE
Foster
A C
AC
Erion
M D
MD
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D003839:Deoxyadenosines / Q000494:pharmacology; D004597:Electroshock; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation; D009043:Motor Activity / Q000187:drug effects; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012640:Seizures / Q000503:physiopathology* / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D000927:Anticonvulsants; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; C108064:GP 683; D011743:Pyrimidines; D011994:Recombinant Proteins; C057928:5'-amino-5'-deoxyadenosine; C034214:5-iodotubercidin; D000248:Adenosine Kinase; D000241:Adenosine; D014372:Tubercidin