Abstract
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.
Footnotes
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Send reprint requests to: James Wiesner, Metabasis Therapeutics, Inc., 9390 Towne Center Drive, San Diego, CA 92121. E-mail: wiesner{at}mbasis.com
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↵1 Presented in part at the meeting of the Society for Neuroscience, October 1995.
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↵2 Present address: Combichem, Inc., 9050 Camino Santa Fe, San Diego, CA 92121.
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↵3 Present address: Cypros Pharmaceutical Corp., 2714 Loker Ave. W., Carlsbad, CA 92008.
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↵4 Present address: LG Biomedical Institute, 3252 Holiday Court, Suite 101, La Jolla, CA 92037.
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↵5 Present address: Intervu, Inc., 201 Lomas Santa Fe Drive, Solana Beach, CA 92075.
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↵6 Present address: Neurocrine Biosciences, Inc., 10555 Science Center Dr., San Diego, CA 92121.
- Abbreviations:
- AK
- adenosine kinase
- ARA
- adenosine-regulating agent
- ADA
- adenosine deaminase
- MES
- maximal electroshock
- HTE
- hindlimb tonic extension
- ITU
- 5-iodotubercidin
- 5′-dITU
- 5′-deoxy-ITU
- 5′-adADO
- 5′-amino-5′-deoxyadenosine
- NBTI
- nitrobenzylthioinosine
- DCF
- 2′-deoxycoformycin
- EHNA
- erythro-9-(2-hydroxy-3-nonyl)adenine
- CPA
- N6-cyclopentyladenosine
- CHA
- [3H]cyclohexyladenosine
- NECA
- [3H]5′-N-ethylcarboxamidoadenosine
- 8-SPT
- 8-(p-sulfophenyl)theophylline
- DMSO
- dimethyl sulfoxide
- CI
- confidence interval
- Received November 12, 1998.
- Accepted February 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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