Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents — preclinical studies

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Abstract

Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-d-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatogolical antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.

References (151)

  • L.-O. Farnebo et al.

    Dopamine and noradrenaline releasing action of amantadine in the central and peripheral nervous system: a possible mode of action in Parkinson's disease

    European Journal of Pharmacology

    (1971)
  • A. Grossmann et al.

    The effect of dimethylaminoadamantane on neuronal membranes

    European Journal of Pharmacology

    (1976)
  • W. Hauber et al.

    The NMDA antagonist dizocipline (MK-801) reverses haloperidol-induced movement initiation deficits

    Behavioral Brain Research

    (1990)
  • R.E. Heikkila et al.

    Evaluation of amantadine as releasing agent or uptake blocker for [3H]dopamine in rat brain slices

    European Journal of Pharmacology

    (1972)
  • M.E. Karobath

    Amantadine and D-145, an amantadine derivative, do not effect dopamine sensitive adenyllate cyclase from the caudate-putamen of the rat brain

    European Journal of Pharmacology

    (1974)
  • G. Keilhoff et al.

    Memantine prevents quinolinic acid-induced hippocampal damage

    European Journal of Pharmacology

    (1992)
  • J. Kornhuber et al.

    Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel—a human postmortem brain study

    European Journal of Pharmacology

    (1991)
  • J. Kornhuber et al.

    Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex

    European Journal of Pharmacology

    (1989)
  • J. Kornhuber et al.

    Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man

    Neuroscience Letters

    (1995)
  • J. Kornhuber et al.

    Therapeutic brain concentration of the NMDA receptor antagonist amantadine

    Neuropharmacology

    (1995)
  • J. Kornhuber et al.

    Affinity of 1-aminoadamantanes for the sigma binding site in post-mortem human frontal cortex

    Neuroscience Letters

    (1993)
  • W. Löscher et al.

    Comparison of competitive and uncompetitive NMDA receptor antagonists with regard to monoaminergic neuronal activity and behavioural effects in rats

    European Journal of Pharmacology

    (1993)
  • H.S. Lustig et al.

    Antiparkinsonian drugs and invitro excitotoxicity

    Brain Research

    (1992)
  • J. Maj et al.

    Pharmacological effects of 1,3-dimethyl-5-aminoadamantane, a new adamantane derivative

    European Journal of Pharmacology

    (1974)
  • K. Masuo et al.

    Effects of memantine on the frog neuromuscular junction

    European Journal of Pharmacology

    (1986)
  • M.K. Menon et al.

    GABA-ergic drugs block the locomotor stimulant effects of 1,3-dimethyl-5-aminoadamantane (D-145)

    Neuropharmacology

    (1979)
  • M.K. Menon et al.

    Pharmacological evidence for the involvement of GABA-ergic system in the locomotor stimulation produced in mice by 1,3-dimethyl-5- aminoadamantane (D-145)

    Neuropharmacology

    (1978)
  • F.S. Messiha

    Effect of amantadine on chlorpromazine and reserpine-induced behavioral depression in the mouse

    Neuroscience and Biobehavioral Reviews

    (1988)
  • M. Misztal et al.

    Learning deficit induced by chronic intraventricullar infusion of quinolinic acid—protection by MK-801 and memantine

    European Journal of Pharmacology

    (1996)
  • K. Mizoguchi et al.

    Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-D-aspartate antagonism

    Brain Research

    (1994)
  • N.N. Osborne et al.

    Memantine stimulates inositol phosphates production in neurones and nullifies N-methyl-D-aspartate-induced destruction of retinal neurones

    Neurochemistry International

    (1992)
  • C.G. Parsons et al.

    Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan)

    Neuropharmacology

    (1993)
  • C.G. Parsons et al.

    Comparison of the potency, kinetics and voltage-dependency of open channel blockade for a series of uncompetitive NMDA antagonists in vitro with anticonvulsive and motor impairment activity in vivo

    Neuropharmacology

    (1995)
  • S.A. Allman et al.

    Evidence that D145 is limbic specific

    British Journal of Pharmacology

    (1982)
  • F.Y. Aoki et al.

    Clinical pharmacokinetics of amantadine hydrochloride

    Clinical Pharmacokinetics

    (1988)
  • F.Y. Aoki et al.

    Amantadine kinetics in healthy young subjects after long-term dosing

    Clinical Pharmacokinetics and Therapeutics

    (1979)
  • F.M. Ashroft et al.

    Amantadine and sparteine inhibit ATP-regulated K-currents in the insulin-secreting beta-cell line

    British Journal of Pharmacology

    (1991)
  • E.V. Bailey et al.

    The mechanism of amantadine in Parkinsonism: a review

    Archives of International Pharmacodynamics

    (1975)
  • W. Birkmayer et al.

    Der 3,4-dioxyphenylalanin (=L-dopa) — Effekt bei der Parkinson akinesie

    Wien Klinik Wochenschrift

    (1961)
  • W.E. Bleidner et al.

    Absorption, distribution and excretion of amantadine hydrochloride

    Journal of Pharmacology and Experimental Therapeutics

    (1965)
  • M. Brenner et al.

    Amantadine sulphate in treating Parkinson's disease: Clinical effects, psychometric tests and serum concentrations

    Journal of Neurology

    (1989)
  • F. Brown et al.

    Studies on the mechanism of action of amantadine

    British Journal of Pharmacology

    (1976)
  • N. Burnashev et al.

    Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor

    Science

    (1992)
  • M. Carlsson et al.

    The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice

    Journal of Neural Transmission

    (1989)
  • H.S.V. Chen et al.

    Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine—t herapeutic advantage against NMDA receptor-mediated neurotoxicity

    Journal of Neuroscience

    (1992)
  • J.D. Clements et al.

    The time course of glutamate in the synaptic cleft

    Science

    (1992)
  • B. Costall et al.

    Neuropharmacological studies on D145 (1,3-dimethyl-5-aminoadamatan)

    Psychopharmacology

    (1975)
  • B. Costall et al.

    The 6-hydroxydopamine rotational model for the detection of dopamine agonist activity: reliability of effect from different locations of 6-hydroxydopamine

    Journal of Pharmacy and Pharmacology

    (1975)
  • W. Danysz et al.

    Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats? Case of amantadine and memantine

    Journal of Neural Transmission [Parkinson's Disease Section]

    (1994)
  • W. Danysz et al.

    Glutamate in CNS disorders — a revived target for drug development

    Drugs News Perspectives

    (1995)
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