Anticonvulsant and antinociceptive actions of novel adenosine kinase inhibitors.
Adenosine (ADO) acts as an inhibitory neuromodulator throughout the central and peripheral nervous system and can regulate seizure and nociceptive activity. However, the positive actions of systemically administered ADO are usually accompanied by undesirable side effects such as hypomobility and cardio-suppression. Adenosine kinase (AK) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. We review the recent development of structurally novel nucleoside and nonnucleoside AK inhibitors that demonstrate high specificity for the AK enzyme. Several of these compounds have shown significant beneficial effects in animal models of epilepsy and pain with an improved preclinical therapeutic window over direct acting ADO receptor agonists.
McGaraughty
Steve
S
Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064-6118, USA. Steve.P.McGaraughty@abbott.com
Cowart
Marlon
M
Jarvis
Michael F
MF
Berman
Robert F
RF
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D010146:Pain / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000700:Analgesics; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D000248:Adenosine Kinase