Anticonvulsant Actions of Novel and Reference Adenosine Agonists

Knutsen, Lars J. S.; Lau, Jesper; Sheardown, Malcolm J.; Eskesen, Karen; Thomsen, C.; Weis, Ján; Judge, Martin E.; Klitgaard, Henrik

doi:10.1007/978-1-4615-2011-5_51

Cited by 10 publications

(14 citation statements)

References 22 publications

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“…This change confers greater lipophilicity to the molecule, to assist it in crossing the blood−brain barrier. Nucleoside 12 is a member of a later compound series compared to 10 , and its pronounced neuroprotective effects have been reported in brief previously. , …”

Section: Resultsmentioning

confidence: 90%

“…6 It is now becoming apparent that adenosine and adenosine receptor ligands have a range of potential applications in the therapy of CNS disorders, 7 since adenosine appears to act as an endogenous neuroprotectant 8 and antiepileptic agent. [9][10][11] Enhanced metabolic activity, with high ATP to ADP turnover, leads in turn to elevated extracellular adenosine levels, 12 which cause hyperpolarization and reduced neuronal firing. Indeed, investigators utilizing microdialysis have measured elevated levels of adenosine postischemia, 13 giving evidence of its apparent endogenous neuroprotective function.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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“…Adenosine agonists, which are almost exclusively derivatives of adenosine (1), have been sought as potential hypotensive (2), antipsychotic (3,4), antiarrhythmic (5), antilipolytic (thus antidiabetic, 6) and cerebroprotective (7)(8)(9)(10) agents. Adenosine antagonists, of which xanthines and a number of fused heterocyclic ring systems are representative (1), have been under development as antiasthmatic (11), antidepressant (12), antiarrhythmic (13), renal protective (14,15), antiparkinson (16) and cognitive enhancing (17)(18)(19) drugs.…”

Section: Introductionmentioning

confidence: 99%

A3-adenosine receptors: Design of selective ligands and therapeutic prospects

Ka¹,

Ho²,

Sm³

et al. 1995

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“…Nevertheless, their clinical implementation was mitigated by cardiovascular and hypotensive side effects (Williams, 1993;White et al, 1996). Recently, new classes of A 1 agonists, devoid of such disturbing issues, have been disclosed (Knutsen et al, 1995;Bischofberger et al, 1997). Among them, ADAC has been studied extensively as a potential candidate for the treatment of ischemia (Von Lubitz et al, 1996a,b, 1999.…”

Section: Discussionmentioning

confidence: 99%

The Adenosine A₁Receptor Agonist Adenosine Amine Congener Exerts a Neuroprotective Effect against the Development of Striatal Lesions and Motor Impairments in the 3-Nitropropionic Acid Model of Neurotoxicity

et al. 2002

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Huntington's disease is a genetic neurodegenerative disorder characterized clinically by both motor and cognitive impairments and striatal lesions. At present, there are no pharmacological treatments able to prevent or slow its development. In the present study, we report the neuroprotective effect of adenosine amine congener (ADAC), a specific A1 receptor agonist known to be devoid of any of the side effects that usually impair the clinical use of such compounds. Remarkably, in a rat model of Huntington's disease generated by subcutaneous infusion of the mitochondrial inhibitor 3-nitropropionic acid (3NP), we have observed that an acute treatment with ADAC (100 microg x kg(-1) x d(-1)) not only strongly reduces the size of the striatal lesion (-40%) and the remaining ongoing striatal degeneration (-30%), but also prevents the development of severe dystonia of hindlimbs. Electrophysiological recording on corticostriatal brain slices demonstrated that ADAC strongly decreases the field EPSP amplitude by 70%, whereas it has no protective effect up to 1 microm against the 3NP-induced neuronal death in primary striatal cultures. This suggests that ADAC protective effects may be mediated presynaptically by the modulation of the energetic impairment-induced striatal excitotoxicity. Altogether, our results indicate that A1 receptor agonists deserve further experimental evaluation in animal models of Huntington's disease.

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Anticonvulsant Actions of Novel and Reference Adenosine Agonists

Cited by 10 publications

References 22 publications

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

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

A3-adenosine receptors: Design of selective ligands and therapeutic prospects

The Adenosine A₁Receptor Agonist Adenosine Amine Congener Exerts a Neuroprotective Effect against the Development of Striatal Lesions and Motor Impairments in the 3-Nitropropionic Acid Model of Neurotoxicity

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Anticonvulsant Actions of Novel and Reference Adenosine Agonists

Cited by 10 publications

References 22 publications

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

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

A3-adenosine receptors: Design of selective ligands and therapeutic prospects

The Adenosine A1Receptor Agonist Adenosine Amine Congener Exerts a Neuroprotective Effect against the Development of Striatal Lesions and Motor Impairments in the 3-Nitropropionic Acid Model of Neurotoxicity

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Product

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About

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

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

The Adenosine A₁Receptor Agonist Adenosine Amine Congener Exerts a Neuroprotective Effect against the Development of Striatal Lesions and Motor Impairments in the 3-Nitropropionic Acid Model of Neurotoxicity