The compound MK-801{(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate)} is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 ± 2.7 nM) binding sites for [3HJMK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites.

Gabapentin (1-(Gabapentin (1-(aminomethyl)cyclohexane acetic acid; Neurontin) is a novel antiepileptic drug that is orally active in various animal models of epilepsy, including maximal electroshock in rats and pentylenetetrazol-or audiogenically induced seizures in mice (1-3). Gabapentin has also been shown to be effective in decreasing the frequency of seizures in medically refractory patients with partial or generalized epilepsy (3, 4). Although originally synthesized as a lipophilic ␥-aminobutyric acid (GABA) 1 analogue, capable of penetrating the blood-brain barrier, gabapentin does not possess a high affinity for either GABA A or GABA B receptors, does not influence neural uptake of GABA and does not inhibit the GABA-metabolizing enzyme, GABA transaminase (EC 2.6.1.19) (3, 5). Moreover, gabapentin does not affect voltage-dependent sodium channels (the site of action of several antiepileptic drugs, including phenytoin, carbamazepine, and valproate) and is inactive in assays for a wide range of other neurotransmitter receptors, enzymes, and ion channels (5, 6).A single high affinity (K D ϭ 38 Ϯ 2.8 nM) binding site for [ 3 H]gabapentin in rat brain has been described (7). Radioligand binding to brain membranes was potently inhibited by a range of gabapentin analogues and by several 3-alkyl-substituted analogues of GABA, although GABA itself was only weakly active. Other antiepileptic drugs including phenytoin, diazepam, carbamazepine, valproate, and phenobarbitone were inactive. Gabapentin (IC 50 ϭ 80 nM) and (RS)-3-isobutyl-GABA (IC 50 ϭ 80 nM) were the most active compounds identified (7). The (Sϩ)-enantiomer of 3-isobutyl-GABA was significantly more active than the (RϪ)-enantiomer both in displacing Despite extensive research the mechanism of action of gabapentin remains unclear. In vivo behavioral studies have suggested the possible involvement of the glycine co-agonist site of the NMDA receptor complex in the anticonvulsant action of gabapentin; intracerebroventricular administration of D-serine (a glycine site agonist) reversed the protection afforded by gabapentin against chemically induced seizures in mice (9). However, radioligand binding assays have not shown gabapentin to inhibit strychnine-insensitive [ 3

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PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with ICSO values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay andKe values of7.82 and 12.9 nM, respectively, in their blocking action on CCK responses in the rat lateral hypothalamic slice. PD134308 and PD135158 produced potent anxiolytic effects in the mouse black/white box test after either subcutaneous or oral administration. There was no evidence of the development of tolerance to the anxiolytic action of either PD134308 or PD135158 in mice treated twice daily for 7 days, nor was there any sign of withdrawal anxiogenesis after abrupt termination of this treatment. Both CCK-B antagonists were able to suppress the withdrawal anxiogenesis and produce an anxiolytic effect in mice previously made tolerant to diazepam. PD134308 and PD135158 produced potent anxiolytic effects in the rat elevated plus maze test and the rat social interaction test. The effects were comparable in magnitude to those seen with diazepam. However, unlike diazepam, PD134308 and PD135158 did not produce sedation. The CCK-B antagonists also showed powerful anxiolytic activity in the "marmoset human threat test." These results provide evidence of a selective role for CCK-B receptors in the control of anxiety.PD134308 and PD135158 are members of a class of anxiolytic agents that have a greatly improved prorfle compared with benzodiazepines or serotonin-related anxiolytics.

The neuroprotective effects of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, were evaluated in models of cerebral ischemia using Mongolian gerbils. Bilateral occlusion of the carotid arteries for a period of 5 min resulted in a consistent pattern of degeneration of hippocampal CA1 and CA2 pyramidal neurons, which was quantified using an image analyzer. Systemic administration of MK-801 (0.01-10 mg/kg, i.p.) 1 hr prior to the occlusion caused a dose-dependent protection of the CA1 and CA2 neurons. The ED50 value for neuroprotection by MK-801 was calculated to be 0.3 mg/kg, and at doses greater than or equal to 3 mg/kg the majority of animals were completely protected against the ischemic insult. Systemic administration of MK-801 (1 or 10 mg/kg, i.p.) 1 hr prior to unilateral occlusion of the right carotid artery resulted in significant protection against hippocampal neurodegeneration following 10 min of occlusion, and increased the survival rate after 30 min of occlusion. The potent neuroprotective effects of MK-801 in these cerebral ischemia models add further weight to the evidence that NMDA receptors are involved in the mechanism of ischemia-induced neuronal degeneration.