Anticonvulsant action of 1,3-dimethyl-5-aminoadamantane

Abstract

The anticonvulsant actions of memantine (1,3-dimethyl-5-aminoadamantane) have been evaluated in mice (seizures induced by maximal electroshock, pentylenetetrazol, bicuculline, picrotoxin, 3-mercaptopropionic acid and N-methyl-D,L-aspartic acid) and in photosensitive baboons, Papio Papio (clonic responses to intermittent photic stimulation). Memantine, 5-20 mg/kg, raised the threshold for electroconvulsions and protected mice against the tonic hind limb extension in pentylenetetrazol-, bicuculline-, picrotoxin- and 3-mercaptopropionic acid-induced seizures, but was ineffective against the clonic phase of chemically-induced seizures. In the baboons, no protection against photomyoclonic responses was observed within 5 h after the intravenous administration of memantine, 1-9 mg/kg. Amantadine, 100 mg/kg, reduced the protective effect of memantine against electroconvulsions. Apomorphine, haloperidol, pimozide, spiroperidol and bicuculline did not modify the anticonvulsant activity of memantine in electroconvulsions. These studies demonstrate an anticonvulsant action of memantine in rodents and suggest that dopaminergic mechanisms do not contribute to its mechanism of action.

Synaptic plasticity in glutamatergic and GABAergic neurotransmission following chronic memantine treatment in an in vitro model of limbic epileptogenesis

“…Thus, moderate-affinity uncompetitive NMDAR antagonists held promise for treatment against numerous neurological disorders, including epilepsy (Chen et al, 1992; Lipton, 1993; Rogawski, 1993; Parsons et al, 1995, 1999). However, although acute memantine administration in in vivo epilepsy models showed anticonvulsive properties, proconvulsive effects also have been reported at 20–60 mg/kg doses (Meldrum et al, 1986; Loscher, 1998; Mareš and Mikulecká, 2009). Chronic treatment with a clinically relevant concentration of memantine also exacerbated seizure-like events (SLE) in an in vitro organotypic hippocampal slice culture model of epileptogenesis (Wang and Bausch, 2004).…”

Mechanism of memantine block of NMDA‐activated channels in rat retinal ganglion cells: uncompetitive antagonism.

“…Structure of memantine Memantine (1-amino-3,5-dimethyladamantane hydrochloride) is known to have anti-Parkinsonian (Schneider, Fischer, Clemens, Balzereit, Funfgeld & Haase, 1984) and anti-epileptic (Meldrum, Turski, Schwarz, Czuczwar & Sontag, 1986) properties. It is an analogue of amantadine, an anti-A2 influenza agent (reviewed in Tominack & Hayden, 1987).…”

“…Here, we use the drug memantine as an example to elucidate the molecular nature of antagonism against NMDA-operated receptors, to establish a stepwise method with molecular schemes to dissect the difference between non-competitive and uncompetitive modes of action, and to outline a molecular basis for evaluating therapeutic advantages among this class of open-channel blockers. NH2 Structure of memantine Memantine (1-amino-3,5-dimethyladamantane hydrochloride) is known to have anti-Parkinsonian (Schneider, Fischer, Clemens, Balzereit, Funfgeld & Haase, 1984) and anti-epileptic (Meldrum, Turski, Schwarz, Czuczwar & Sontag, 1986) properties. It is an analogue of amantadine, an anti-A2 influenza agent (reviewed in Tominack & Hayden, 1987).…”

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

“…Memantine (I-amino-3,%dimethyladamantane hydrochloride) is known to have anti-Parkinsonian (Schneider et al, 1984) and anti-epileptic (Meldrum et al, 1986) properties and is an analog ofamantadine (1 -adamantanamine hydrochloride), a wellknown antiviral agent (Zlydnikov et al,198 1). Both adamantane derivatives have been used clinically for Parkinson's disease for many years in the United States or in Europe (Schwab et al, 1969;Schneider et al, 1984).…”