Adenosinergic modulation of the EEG and locomotor effects of the A2 agonist, CGS 21680

Janusz, Cynthia A.; Berman, Robert F.

doi:10.1016/0091-3057(93)90139-k

Cited by 15 publications

(5 citation statements)

References 26 publications

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“…It is interesting to note the lack of effect of CPX alone. A similar result was obtained by Griebel et al (1991) (Barraco et al, 1983;Durcan & Morgan 1989;Jacobson et al, 1991;Janusz & Berman 1993), this result is entirely consistent with an ability of caffeine to block A2 receptors tonically activated by endogenous adenosine. This explanation of the anxiogenic-like activity of caffeine, that simultaneous Al and A2 receptor blockade is necessary for anxiogenesis, is in accord with the finding of Griebel et al (1991) that the non-xanthine antagonist, CGS15943A, which also possesses the ability to block both Al and A2 receptors, also showed anxiogenic activity.…”

Section: Discussionsupporting

confidence: 75%

Anxiolytic activity of adenosine receptor activation in mice

Jain

Kemp

Adeyemo

et al. 1995

British J Pharmacology

112

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1 Purine analogues have been examined for anxiolytic-and anxiogenic-like activity in mice, by use of the elevated plus-maze.2 The selective Al receptor agonist, N6-cyclopentyladenosine (CPA) had marked anxiolytic-like activity at 1O and 50 gg kg-, with no effect on locomotor performance at these doses.3 The Al selective adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (CPX) had no significant effect on anxiety-related measures or locomotor behaviour, but blocked the anxiolytic-like activity of CPA. The hydrophilic xanthine, 8-(p-sulphophenyl) theophylline did not prevent anxiolysis by CPA. 4 Caffeine had anxiogenic-like activity at 30 mg kg-' which was prevented by CPA at 50 Yg kg-. 5The A2 receptor agonist, Nl-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg-'. The A2 receptor antagonist, 1,3-dimethyl-1-propargylxanthine (DMPX) had no effect on anxiety-related measures or locomotion and did not modify the anxiolytic-like activity of CPA. 6 Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic-like activity of the latter.7 The results suggest that the selective activation of central Al adenosine receptors induces anxiolyticlike behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of Al receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus-maze in mice are not activated tonically by endogenous adenosine.

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Section: Discussionsupporting

confidence: 75%

Anxiolytic activity of adenosine receptor activation in mice

Jain

Kemp

Adeyemo

et al. 1995

British J Pharmacology

112

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“…It has been shown previously that adenosine receptor agonists are potent locomotor depressants, 11,44,67,68 and although most studies have been carried out on A 1 agonists, the A 2A agonist CGS 21680 (33) has also been shown previously to possess this property. 69 The data in Table 2 indicate that the five novel adenosine agonists with diminished cardiovascular effects also have markedly less inhibitory effect on spontaneous locomotor activity than the eight reference compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Mouse Locomotor Activity. ,, Male NMRI mice (Moellegaard's Breeding Labs, Ll. Skensved, Denmark) weighing an average of 25 g were used.…”

Section: Experimetal Sectionmentioning

confidence: 99%

N-Substituted Adenosines as Novel Neuroprotective A₁ Agonists with Diminished Hypotensive Effects

et al. 1999

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The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A(1) agonists with potent central nervous system effects and diminished influence on the cardiovascular system are reported and compared to selected reference adenosine agonists. The novel compounds featured are derived structurally from two key lead structures: 2-chloro-N-(1-phenoxy-2-propyl)adenosine (NNC 21-0041, 9) and 2-chloro-N-(1-piperidinyl)adenosine (NNC 90-1515, 4). The agonists are characterized in terms of their in vitro profiles, both binding and functional, and in vivo activity in relevant animal models. Neuroprotective properties assessed after postischemic dosing in a Mongolian gerbil severe temporary forebrain ischemia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an A(1) functional assay show similarities to some reference adenosine agonists. However, the new compounds we describe exhibit diminished cardiovascular effects in both anesthetized and awake rats when compared to reference A(1) agonists such as (R)-phenylisopropyladenosine (R-PIA, 5), N-cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR 79236, 26), N-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl]adenosine (Metrifudil, 28). In mouse permanent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine (NNC 21-0136, 12) exhibited significant neuroprotection at the remarkably low total intraperitoneal dose of 0.1 mg/kg, a dose at which no cardiovascular effects are observed in conscious rats. The novel agonists described inhibit 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED(50) values than for reference A(1) agonists. We conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1-piperidinyl]adenosine (NNC 21-0147, 13), representatives of a new series of P(1) ligands, reinforce the fact that novel selective adenosine A(1) agonists have potential in the treatment of cerebral ischemia in humans.

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“…For direct intrastriatal or intranigral infusion, drugs were diluted with water to their final concentration in 10% ␤-CD. Systemic and intracranial doses of CPX and DMPX used in the present study are known to have selectivity for A 1 and A 2a receptors, respectively, in the brain (Janusz and Berman, 1993;Phillis, 1995;Reggio et al, 1999;Chen et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

Adenosinergic Protection of Dopaminergic and GABAergic Neurons against Mitochondrial Inhibition through Receptors Located in the Substantia Nigra and Striatum, Respectively

et al. 2003

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Mitochondrial dysfunction may contribute to dopaminergic (DAergic) cell death in Parkinson's disease and GABAergic cell death in Huntington's disease. In the present work, we tested whether blocking A1 receptors could enhance the damage to DAergic and GABAergic neurons caused by mitochondrial inhibition, and whether blocking A2a receptors could protect against damage in this model. Animals received an intraperitoneal injection of 8-cyclopentyl-1,3-dipropylxanthine (CPX) (A1 antagonist) or 3,7-dimethyl-1-propargylxanthine (DMPX) (A2a antagonist) 30 min before intrastriatal infusion of malonate (mitochondrial complex II inhibitor). Damage was assessed 1 week later by measuring striatal dopamine, tyrosine hydroxylase (TH), and GABA content. In mice and rats, malonate-induced depletion of striatal dopamine, TH, or GABA was potentiated by pretreatment with 1 mg/kg CPX and attenuated by pretreatment with 5 mg/kg DMPX. To determine the location of the A1 and A2a receptors mediating these effects, CPX or DMPX was infused directly into the striatum or substantia nigra of rats 30 min before intrastriatal infusion of malonate. When infused into the striatum, CPX (20 ng) potentiated, whereas DMPX (50 ng) prevented malonate-induced GABA loss, but up to 100 ng of CPX or 500 ng of DMPX did not alter malonate-induced striatal dopamine loss. Intranigral infusion of CPX (100 ng) or DMPX (500 ng), however, did exacerbate and protect, respectively, against malonate-induced striatal dopamine loss. Thus, A1 receptor blockade enhances and A2a receptor blockade protects against damage to DAergic and GABAergic neurons caused by mitochondrial inhibition. Interestingly, these effects are mediated by A1 and A2a receptors located in the substantia nigra for DAergic neurons and in the striatum for GABAergic neurons.

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Adenosinergic modulation of the EEG and locomotor effects of the A2 agonist, CGS 21680

Cited by 15 publications

References 26 publications

Anxiolytic activity of adenosine receptor activation in mice

Anxiolytic activity of adenosine receptor activation in mice

N-Substituted Adenosines as Novel Neuroprotective A₁ Agonists with Diminished Hypotensive Effects

Adenosinergic Protection of Dopaminergic and GABAergic Neurons against Mitochondrial Inhibition through Receptors Located in the Substantia Nigra and Striatum, Respectively

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Adenosinergic modulation of the EEG and locomotor effects of the A2 agonist, CGS 21680

Cited by 15 publications

References 26 publications

Anxiolytic activity of adenosine receptor activation in mice

Anxiolytic activity of adenosine receptor activation in mice

N-Substituted Adenosines as Novel Neuroprotective A1 Agonists with Diminished Hypotensive Effects

Adenosinergic Protection of Dopaminergic and GABAergic Neurons against Mitochondrial Inhibition through Receptors Located in the Substantia Nigra and Striatum, Respectively

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N-Substituted Adenosines as Novel Neuroprotective A₁ Agonists with Diminished Hypotensive Effects