l-701324 and eliprodil

The discovery that glutamate's activity at the N-methyl-D-aspartate (NMDA) receptor is positively modulated by glycine and polyamines has led to a new pharmacological strategy that NMDA receptor-mediated events could be antagonized indirectly at the strychnine-insensitive glycine co-agonist site (glycine(B) receptor) and the polyamine modulatory site. Recently we demonstrated that ifenprodil and L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinoline), polyamine and glycine, receptor antagonists, respectively, at subeffective doses markedly increased after-discharge threshold (ADT) when applied together in amygdala-kindled rats. Because ifenprodil and its derivative, eliprodil, exhibit different affinities for NMDA receptors composed of different subunits, our current question was whether a combination of eliprodil and the glycine, receptor antagonist, L-701,324, would produce a super-additive anticonvulsant action. In addition, we examined the combined treatment of eliprodil with a competitive NMDA receptor antagonist CGP 40116 (D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) in the kindling model. Eliprodil alone (10-40 mg/kg) had no consistent ADT-increasing activity. When eliprodil was combined with an ineffective dose of L-701,324 (2.5 mg/kg), a significant rise in ADT was observed. Likewise, other measures of seizure activity such as severity and duration were modestly but significantly reduced. With respect to behavioral impairments, no signs of synergistic interaction were observed after the drug combinations. On the other hand, no anticonvulsant effects were found when CGP 40116 was administered alone at doses of 1.25-5 mg/kg or CGP 40116 1.25 mg/kg combined with eliprodil 10 mg/kg. These data suggest that combination therapy with antagonists at the polyamine and glycine sites might potentially treat therapy-resistant complex partial seizures.

Topics: 2-Amino-5-phosphonovalerate; Amygdala; Animals; Anticonvulsants; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Kindling, Neurologic; Piperidines; Quinolones; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

The ethanol-like discriminative stimulus properties of a novel NMDA glycine receptor antagonist, L-701,324 ((7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone), a polyamine receptor antagonist, eliprodil, and a non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), were examined in rats trained to discriminate ethanol from vehicle in a two-lever discrimination procedure. In rats trained to discriminate ethanol from vehicle, L-701,324 and MK-801 substituted for ethanol in a dose-dependent fashion with a complete substitution noted following administration of 7.5 mg/kg L-701,324 and 0.2 mg/kg MK-801, respectively. Full substitution for ethanol was achieved with no alteration in the rate of responding. In contrast, administration of eliprodil (in doses up to 5 mg/kg) showed only a partial, but not dose-dependent, substitution for ethanol. These findings indicate that a reduction of NMDA receptor activity, produced either via a blockade of non-competitive NMDA recognition sites or of NMDA/glycine-sensitive regulatory sites, had discriminative stimulus properties that are similar to those produced by ethanol. Furthermore, the observation that the NMDA/glycine receptor antagonist, L-701,324, was a more effective substitute for ethanol than was the polyamine antagonist, eliprodil, suggests that several NMDA receptor subunits, and thus not only NMDAR2B receptor subunits, are of importance for the discriminative stimulus effects of ethanol.

Topics: Administration, Oral; Animals; Behavior, Animal; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Antagonists; Male; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.

Topics: Acoustic Stimulation; Administration, Oral; Animals; Anticonvulsants; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Seizures; Substance Withdrawal Syndrome