Recent developments in the discovery of novel adenosine kinase inhibitors: mechanism of action and therapeutic potential.
Adenosine (ADO) is an endogenous inhibitory neuromodulator that limits cellular excitability in response to tissue trauma and inflammation. Adenosine kinase (AK; EC 2.7.1.20) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. AK inhibitors have been shown to significantly increase ADO concentrations at sites of tissue injury and to provide effective antinociceptive, antiinflammatory, and anticonvulsant activity in animal models. Structurally novel nucleoside and non-nucleoside AK inhibitors that demonstrate high specificity for the AK enzyme compared with other ADO metabolic enzymes, transporters, and receptors have recently been synthesized. These compounds have also demonstrated improved cellular and tissue penetration compared with earlier tubercidin analogs. These compounds have been shown to exert beneficial effects in animal models of pain, inflammation and epilepsy with reduced cardiovascular side effects compared with direct acting ADO receptor (P1) agonists, thus supporting the hypothesis that AK inhibitors can enhance the actions of ADO in a site- and event-specific fashion.
McGaraughty
S
S
Neuroscience, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA.
Cowart
M
M
Jarvis
M F
MF
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009705:Nucleosides; D011743:Pyrimidines; D000248:Adenosine Kinase; D000241:Adenosine