Inhibition of adenosine kinase and adenosine uptake in guinea-pig CNS tissue by halogenated tubercidin analogues

doi:10.1016/0024-3205(95)00099-2

Life Sciences

Volume 56, Issue 17, 17 March 1995, Pages PL345-PL349

https://doi.org/10.1016/0024-3205(95)00099-2 Get rights and content

Abstract

Two halogenated analogues of tubercidin (7-deazaadenosine) viz. 5-iodotubercidin and 5′-deoxy-5-iodotubercidin, previously were shown to be potent inhibitors of guinea-pig brain adenosine kinase activity and adenosine uptake in guinea-pig cerebral cortex slices. A further series of halogenated tubercidin analogues have been investigated; of the 9 compounds tested, 5′-deoxy-5-iodotubericidin was the most potent adenosine kinase inhibitor while 5-iodotubercidin was the most potent in inhibiting the facilitated uptake of adenosine. These compounds may be useful for elucidating the involvement of adenosine kinase in adenosine uptake, the maintenance of intracellular adenosine levels and in the neuromodulatory actions of adenosine in the CNS.

References (15)

L.P. Davies et al.
Biochem. Pharmacol.
(1984)
L.P. Davies et al.
Biochem. Pharmacol.
(1986)
L.P. Davies et al.
Gen. Pharmacol.
(1983)
L.P. Davies et al.
Neurochem. Int.
(1986)
L.P. Davies et al.
Neurochem. Int.
(1987)
P.H. Wu et al.
Gen. Pharmacol.
(1984)
M. Williams
Ann. Rev. Pharmacol. Toxicol.
(1987)

There are more references available in the full text version of this article.

Cited by (14)

Advances in algal drug research with emphasis on enzyme inhibitors
2014, Biotechnology Advances
Citation Excerpt :
The halogenated tubercidin analogue, 5-deoxy-5-iodotubercidin (84) derived from brown alga Hypnea valentia inhibited adenosine kinase. This compound was reported as a potent inhibitor of adenosine kinase (Davies and Cook, 1995; Jarvis et al., 2000). This compound has been tested for its use in the treatment of cancer and brain diseases.
Enzyme inhibitors are now included in all kinds of drugs essential to treat most of the human diseases including communicable, metabolic, cardiovascular, neurological diseases and cancer. Numerous marine algae have been reported to be a potential source of novel enzyme inhibitors with various pharmaceutical values. Thus, the purpose of this review is to brief the enzyme inhibitors from marine algae of therapeutic potential to treat common diseases. As per our knowledge this is the first review for the potential enzyme inhibitors from marine origin. This review contains 86 algal enzyme inhibitors reported during 1989–2013 and commercial enzyme inhibitors available in the market. Compounds in the review are grouped according to the disease conditions in which they are involved; diabetes, obesity, dementia, inflammation, melanogenesis, AIDS, hypertension and other viral diseases. The structure-activity relationship of most of the compounds are also discussed. In addition, the drug likeness properties of algal inhibitors were evaluated using Lipinski's 'Rule of Five'.
Effect of adenosine kinase, adenosine deaminase and transport inhibitors on striatal dopamine and stereotypy after methamphetamine administration
2000, Neuropharmacology
The effect of adenosine kinase (AKA), adenosine deaminase (ADA) and transport inhibitors on the release of dopamine (DA) induced by methamphetamine (MTH) in rat striatum was assessed using in vivo microdialysis in freely moving rats. MTH injected in a dose of 3×5 mg/kg i.p. at 2-hour intervals produced a massive release of DA. This excessive release of DA was inhibited by the ADA inhibitor 2′-deoxycoformycin (DCF), the AKA inhibitor 5′-iodotubercidin (IOT) and the adenosine uptake inhibitor dilazep (DIL), each of them given locally to the striatum via a microdialysis probe at a concentration of 100 μM. Perfusion with the same concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 5′-amino-5′-deoxyadenosine (NH₂dAD), ADA and AKA inhibitors, respectively, induced a considerably weaker effect on DA release. The non-selective antagonist of adenosine A₁/A_2A receptor caffeine (75 μM) significantly prevented the inhibitory effect of DCF, IOT and DIL on the MTH-induced DA release. Intrastriatal administration of DCF, IOT and DIL (5 nmol/μl before each injection of MTH) inhibited the stereotypy induced by MTH. The striatal content of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), decreased by MTH administration and measured 5 days after treatment with the toxin, was reversed by all the inhibitors at the order of potency as follows: IOT>DCF>DIL. Direct agonists of adenosine A₁ and A₁/A_2A receptors, N⁶-cyclopentyladenosine (CPA) and 5′-N-ethylcarboxamidoadenosine (NECA), respectively, given intrastriatally (5 nmol/μl) completely abolished the MTH-induced stereotypy and the fall in the striatal content of DA, DOPAC and HVA. The above results show that augmentation of endogenous adenosine in rat striatum by inhibition of its metabolism or uptake—despite the differences in the efficacy of various inhibitors—may provide neuroprotection against a toxic action of MTH.
Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat
1998, Pain
The present study examined the spinal antinociceptive effects of adenosine analogs and inhibitors of adenosine kinase and adenosine deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of adenosine kinase inhibitors by an adenosine deaminase inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 μl), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7–10 days prior to drug testing (antagonist experiments). N⁶-cyclohexyladenosine (CHA; adenosine A₁ receptor agonist; 0.01–1 nmol), 2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine (CGS21680; adenosine A_2A receptor agonist; 0.1–10 nmol), 5′-amino-5′-deoxyadenosine (NH₂dAdo; adenosine kinase inhibitor; 10–300 nmol), and 5-iodotubercidin (ITU; adenosine kinase inhibitor; 0.1–100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2′-deoxycoformycin (dCF; an adenosine deaminase inhibitor; 100–300 nmol). Reversal of drug effects by caffeine (non-selective adenosine A₁/A₂ receptor antagonist; 515 nmol) confirmed the involvement of the adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A₁ receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; adenosine A_2A receptor antagonist; 242 nmol), evidenced an adenosine A₁ receptor mediated spinal antinociception by NH₂dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH₂dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting adenosine agents, when administered spinally, produce antinociception through activation of spinal adenosine A₁ receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected adenosine kinase inhibitors can be significantly augmented when administered simultaneously with an adenosine deaminase inhibitor.
Role of Adenosine as a Modulator of Synaptic Activity in the Central Nervous System
1997, Advances in Pharmacology
Adenosine exerts physiological effects on the nervous system through interactions with cell surface receptors. In the nervous system adenosine has been shown to alter levels of cyclic adenosine 3', 5’-monophosphate (CAMP), inhibit synaptic activity and neuronal excitability, and modulate cerebral blood flow, and these effects have led to numerous proposed functional roles for adenosine. Adenosine can act as a “retaliatory metabolite” by which cells communicate their energy status to the surrounding tissues. Adenosine has been shown to be released during cerebral ischemia, and it increases cerebral blood, inhibits synaptic activity, and decreases neuronal excitability. Thus adenosine acts as a neuroprotectant, preventing damage from ischemia and excitotoxicity. Adenosine receptors are located throughout the nervous system and extracellular adenosine can effectively modulate neuronal activity. This chapter summarizes what is known about how adenosine exerts it effects on neuronal activity, how cells form adenosine and regulate adenosine concentrations, and how cells release adenosine into the extracellular space where it can exert its modulator actions. By integrating these different areas of research, it is hoped that a more complete picture of how the brain uses adenosine as a modulator of synaptic activity will be formed. The chapter discusses the various adenosine receptors, adenosine formation by S-adenosylhomocysteine hydrolase, adenosine formation metabolism of lntracellular nucleotides, degradation of adenosine, adenosine levels in the brain, extracellular degradation of nucleotides, direct release of adenosine into the extracellular space, and localized adenosine release and synaptic modulation. The experimental evidence has made it clear that adenosine serves multiple functions throughout the nervous system. Studies on the actions of exogenous adenosine have conclusively shown that adenosine can act as a potent and effective modulator of synaptic activity and neuronal function. The purpose of the chapter to summarize what is known about how cells synthesize, release, and regulate adenosine.
Efficient and practical synthesis of 5′-deoxytubercidin and its analogues via Vorbrggen glycosylation
2011, Synthesis
Renal interstitial adenosine metabolism during ischemia in dogs
2001, American Journal of Physiology - Renal Physiology

View all citing articles on Scopus

View full text

Pharmacology letter Accelerated communicationInhibition of adenosine kinase and adenosine uptake in guinea-pig CNS tissue by halogenated tubercidin analogues

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Gen. Pharmacol.

Neurochem. Int.

Neurochem. Int.

Gen. Pharmacol.

Ann. Rev. Pharmacol. Toxicol.

Pharmacology letter Accelerated communication
Inhibition of adenosine kinase and adenosine uptake in guinea-pig CNS tissue by halogenated tubercidin analogues