dizocilpine-maleate and milacemide

Twenty four hours after mice were forced to swim for up to 10 minutes in cold water, there was a reduction in the ability of MK-801 to antagonize the electrical precipitation of tonic hindlimb extension. Milacemide, a lipophilic prodrug of glycine, restored the antiseizure efficacy of MK-801 to the same level observed in unstressed animals treated with milacemide and MK-801. Stimulation of the glycine-gated chloride ionophore subsequent to the liberation of free glycine could explain milacemide's pharmacologic action as an adjuvant to MK-801. Consistent with this interpretation, milacemide was able to potentiate the antiseizure effects of flurazepam, a benzodiazepine agonist, in stressed and unstressed mice and carbamazepine in unstressed animals. D-cycloserine, a partial glycine agonist with greater specificity for the strychnine-insensitive modulatory site on the NMDA receptor complex, was examined for its effect on MK-801's antiseizure efficacy. At a high dose (320 mg/kg), D-cycloserine alone had an anticonvulsant effect. Moreover, this dose of D-cycloserine administered with MK-801 showed a significantly greater anticonvulsant efficacy than MK-801 alone. The data support the development of glycinergic interventions as adjunctive agents in the pharmacotherapy of seizure disorders.

Topics: Acetamides; Animals; Anticonvulsants; Carbamazepine; Cycloserine; Dizocilpine Maleate; Drug Synergism; Flurazepam; Male; Mice; Prodrugs; Receptors, Glycine

Milacemide, an acylated prodrug of glycine, was able to increase the efficacy with which [+]-5-methyl-10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5,10-imine meleate (MK 801) antagonized the electrical precipitation of seizures in mice. The mechanism of milacemide's potentiation of MK 801's antiseizure efficacy in intact mice is unclear; however, a glycine agonist selective for the strychnine-insensitive site on the NMDA receptor complex was also able to potentiate MK 801. The exciting possibility exists that an exogenous glycinergic intervention can potentiate NMDA-mediated neural transmission in intact animals.

Topics: Acetamides; Animals; Behavior, Animal; Cycloserine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Electroshock; Glycine; Hindlimb; Male; Mice; Monoamine Oxidase Inhibitors; Reflex

We have investigated the interactions of polyamines and the N-methyl-D-aspartate (NMDA) receptor antagonist ifenprodil with the binding of [3H]MK801 to the NMDA receptor. Spermine and spermidine but not putrescine substantially increase [3H]MK801 binding to well washed rat brain membranes in the absence or presence of saturating concentrations of glutamate and glycine. Spermine also increased the association and dissociation of [3H]MK801 from its binding site, suggesting that polyamines activate the NMDA receptor in a similar manner to glycine. Ifenprodil inhibited the binding of [3H]MK801 in a biphasic fashion. The high affinity phase of binding (Ki of approximately 15 nM) accounted for 50-60% of total [3H]MK801 binding in the nominal absence of glutamate, glycine, and polyamines or in the presence of 100 microM glutamate. This fraction was reduced to 20% by the addition of 30 microM glycine and could be abolished by the addition of 50 microM spermine. However, ifenprodil apparently did not act by binding to the polyamine recognition site. The low affinity phase (Ki of 20-40 microM) was insensitive to the presence of positive modulators and may represent binding to the Zn2+ regulatory site. Ifenprodil decreased NMDA and glycine-induced Ca2+ influx into cultured rat brain neurons. The potency of ifenprodil suggests that spermine may activate NMDA receptors in vivo. These data indicate that ifenprodil may bind to the NMDA receptor in a state-dependent fashion and preferentially stabilize an inactivated form of the channel.

Topics: Acetamides; Animals; Aspartic Acid; Brain; Calcium; Cell Membrane; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Glycine; In Vitro Techniques; Ketamine; Kinetics; N-Methylaspartate; Phencyclidine; Piperidines; Polyamines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

Our understanding of how new antiepileptic drugs work mirrors what we know about how currently marketed antiepileptic compounds exert their action--that information is scarce and elusive. The mechanism of action of antiepileptic drugs is nevertheless inextricably linked to epileptogenesis itself, and investigations of several promising new compounds are underway to establish the levels at which these drugs act. Compounds act on synapses and membranes as well as affecting receptors, neurotransmitters, and peptides. The most extensive data are available on drugs that inhibit the action of GABA or its receptors, including new benzodiazepine-like agents and barbituric-acid derivatives. The few drugs that act by inhibiting the effects of excitatory amino acids are reviewed. Finally, the maximal electroshock test is an empirical method to determine the antiepileptic properties of a drug; several agents under development have been effective in this screening technique.

Topics: Acetamides; Acetates; Amines; Aminocaproates; Aminopyridines; Anti-Anxiety Agents; Anticonvulsants; Aspartic Acid; Benzodiazepines; Benzodiazepinones; Clobazam; Cyclohexanecarboxylic Acids; Dibenzocycloheptenes; Dizocilpine Maleate; Epilepsy; Felbamate; Flumazenil; GABA Antagonists; Gabapentin; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Imidazoles; Lamotrigine; Phenylcarbamates; Propylene Glycols; Receptors, GABA-A; Triazines; Vigabatrin