Partial adenosine A1 receptor agonists inhibit sarin-induced epileptiform activity in the hippocampal slice

Harrison, Patrick K.; Bueters, Tjerk; IJzerman, Adriaan P.; Helden, H.P.M. van; Tattersall, J.E.H.

doi:10.1016/s0014-2999(03)01783-7

Cited by 15 publications

(6 citation statements)

References 37 publications

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“…A 1 AR agonists hold interest therapeutically for their cardio- and neuroprotective, antiarrhythmic, antiseizure, antilipolytic, antiglaucoma, and anxiolytic actions. Some of the novel derivatives were partial A 1 AR agonists, which are of interest for both cerebroprotective and cardiovascular application, depending on levels of endogenous adenosine and on receptor reserve. ,, It is conceivable that the expanded range of physical properties in the present series of truncated derivatives would offer pharmacokinetic advantages. Therefore, this approach is appealing for preclinical development.…”

Section: Discussionmentioning

confidence: 99%

Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

et al. 2012

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A1 adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N6-cycloalkylmethyl 4′-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N6-dicyclopropylmethyl, Ki 47.9 nM) as a moderately A1AR-selective full agonist. Two stereochemically defined N6-methynyl group substituents displayed narrow SAR; larger than cyclobutyl greatly reduced AR affinity, and larger or smaller than cyclopropyl reduced A1AR selectivity. Nucleoside docking to A1AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger “A” forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39) and carbon chains of glutamates (EL2), and smaller subpocket “B” between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A1AR agonists. Truncated nucleosides, an appealing preclinical approach, have more drug-like physicochemical properties than other A1AR agonists. Thus, we identified highly restricted regions for substitution around N6 suitable for an A1AR agonist with anticonvulsant activity.

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Section: Discussionmentioning

confidence: 99%

Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

et al. 2012

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“…Our data support a powerful antiepileptic effect of adenosine via A1AR early after experimental TBI. A rich literature over the past 20 years strongly supports an important role for adenosine—acting at A1AR as an endogenous anticonvulsant across experimental models of epilepsy (Dragunow et al , 1985; Murray et al , 1985; Barraco et al , 1986; von Lubitz et al , 1994; Pourgholami et al , 1997 a , b ; Harrison et al , 2003; Gouder et al , 2004). Although both adenosine acting at the A1AR and γ -aminobutyric acid (GABA) share key roles in maintaining inhibitory tone, it has been suggested that adenosine is the endogenous agent responsible for seizure arrest in a number of paradigms (Knutsen and Murray, 1997; Avsar and Empson, 2004).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A1 Receptor Knockout Mice Develop Lethal Status Epilepticus after Experimental Traumatic Brain Injury

Kochanek

Vagni

Janesko

et al. 2006

J Cereb Blood Flow Metab

172

130

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Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy--and inhibits progression to status epilepticus (SE). Seizures after traumatic brain injury (TBI) may contribute to pathophysiology. Thus, we hypothesized that endogenous adenosine, acting via A1 receptors, mediates antiepileptic benefit after experimental TBI. We subjected A1-receptor knockout (ko) mice, heterozygotes, and wild-type (wt) littermates (n=115) to controlled cortical impact (CCI). We used four outcome protocols in male mice: (1) observation for seizures, SE, and mortality in the initial 2 h, (2) assessment of seizure score (electroencephalogram (EEG)) in the initial 2 h, (3) assessment of mortality at 24 h across injury levels, and (4) serial assessment of arterial blood pressure, heart rate, blood gases, and hematocrit. Lastly, to assess the influence of gender on this observation, we observed female mice for seizures, SE, and mortality in the initial 2 h. Seizure activity was noted in 83% of male ko mice in the initial 2 h, but was seen in no heterozygotes and only 33% of wt (P<0.05). Seizures in wt were brief (1 to 2 secs). In contrast, SE involving lethal sustained (>1 h) tonic clonic activity was uniquely seen in ko mice after CCI (50% incidence in males), (P<0.05). Seizure score was twofold higher in ko mice after CCI versus either heterozygote or wt (P<0.05). An injury-intensity dose-response for 24 h mortality was seen in ko mice (P<0.05). Physiologic parameters were similar between genotypes. Seizures were seen in 100% of female ko mice after CCI versus 14% of heterozygotes and 25% wt (P<0.05) and SE was restricted to the ko mice (83% incidence). Our data suggest a critical endogenous anticonvulsant action of adenosine at A1 receptors early after experimental TBI.

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“…Intracerebral microdialysis studies revealed that survival of sarin-poisoned animals treated with CPA coincided with a minor elevation of extracellular ACh concentrations in the brain relative to the baseline value, whereas an 11-fold increase in transmitter levels was observed in animals not treated with CPA (Bueters et al 2002). The finding that application of CPA to an in vitro hippocampal slice system arrested, in a concentrationrelated manner, epileptiform activity induced by sarin or soman strongly supported this concept (Harrison et al 2003). However, we have also demonstrated that CPA treatment influenced the distribution of sarin within the body, thereby conserving enough AChE activity in the brain to prevent ACh accumulation in central cholinergic synapses in cases of sarin poisoning .…”

Section: Discussionmentioning

confidence: 80%

Cardiovascular effects of the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

Joosen¹,

Bueters²,

Helden³

2003

Arch Toxicol

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Mortality and occurrence of cholinergic symptoms upon sarin intoxication (144 micro g/kg s.c., approximately 2 x LD50) in rats is completely prevented by treatment with the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA, 2 mg/kg i.m.). Previously, we have shown that CPA treatment altered the distribution of sarin into the brain, presumably through its cardiovascular side effects. Therefore, the objective of the present study was to evaluate the contribution of the cardiodepressant effects of CPA to its therapeutic efficacy against sarin intoxication. Intramuscular treatment of rats with 0.5 and 2.0 mg/kg CPA 1 min after sarin poisoning attenuated most cholinergic symptoms and prevented mortality, which seemed to be directly associated with an immediate strong and long-lasting bradycardia and hypotension caused by CPA. Treatment with lower doses of CPA (0.1 and 0.05 mg/kg i.m.) caused similar levels of bradycardia and hypotension, albeit a few minutes later than at the higher doses of CPA. Upon sarin intoxication, this was correlated with increased incidence of cholinergic symptoms and decreased survival rates. Pretreatment with the peripheral adenosine A1 receptor antagonist 8- p-sulphophenyltheophylline (8-PST, 20 mg/kg i.p.) counteracted the cardiodepressant effects of 0.05 mg/kg CPA almost completely, thereby nearly abolishing its therapeutic efficacy against sarin poisoning. In conclusion, the present results strongly indicate that bradycardia and hypotension induced by the peripheral adenosine A1 receptor play a prominent role in the therapeutic efficacy of CPA in cases of sarin poisoning.

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Partial adenosine A1 receptor agonists inhibit sarin-induced epileptiform activity in the hippocampal slice

Cited by 15 publications

References 37 publications

Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Adenosine A1 Receptor Knockout Mice Develop Lethal Status Epilepticus after Experimental Traumatic Brain Injury

Cardiovascular effects of the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

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Partial adenosine A1 receptor agonists inhibit sarin-induced epileptiform activity in the hippocampal slice

Cited by 15 publications

References 37 publications

Structural Sweet Spot for A1 Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Structural Sweet Spot for A1 Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Adenosine A1 Receptor Knockout Mice Develop Lethal Status Epilepticus after Experimental Traumatic Brain Injury

Cardiovascular effects of the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

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Product

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Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity