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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1. An inositol monophosphatase was purified to homogeneity from bovine brain. 2. The enzyme is a dimer of subunit Mr 29,000. 3. The enzyme hydrolyses both enantiomers of myo-inositol 1-phosphate and both enantiomers of myo-inositol 4-phosphate, but has no activity towards inositol bisphosphates, inositol trisphosphates or inositol 1,3,4,5-tetrakisphosphate. 4. Several non-inositol-containing monophosphates are also substrates. 5. The enzyme requires Mg2+ for activity, and Zn2+ supports activity to a small extent. 6. Other bivalent cations (including Zn2+) are inhibitors, competitive with Mg2+. 7. Phosphate, but not inositol, is an inhibitor competitive with substrate. 8. Li+ inhibits hydrolysis of inositol 1-phosphate and inositol 4-phosphate uncompetitively with different apparent Ki values (1.0 mM and 0.26 mM respectively).

Membrane preparations from striatum of pig brain contain endopeptidase activity towards iodoinsulin B-chain. Only 50% of the hydrolysis of insulin B-chain is inhibitable by phosphoramidon, and DEAE-cellulose chromatography can resolve the phosphoramidon-sensitive and -insensitive activities. The former activity (now designated 'endopeptidase-24.11') is responsible for hydrolysis of [D-Ala2,Leu5]enkephalin and is identical with an enzyme in brain that has previously been referred to as 'enkephalinase'. Pig striatal endopeptidase-24.11 has now been purified to homogeneity in a single step by immunoadsorbent chromatography using a monoclonal antibody. The overall purification was 23 000-fold, with a yield of 30%. The brain enzyme appears to be identical with kidney endopeptidase-24.11 in amino acid composition as well as by immunological and kinetic criteria. However, it differs slightly in apparent subunit size (Mr = 87 000), attributable to differences in glycosylation.

As part of a program to investigate the structure-activity relationships of Gabapentin (Neurontin), a number of alkylated analogues were synthesized and evaluated in vitro for binding to the Gabapentin binding site located on the alpha2delta subunit of a calcium channel. A number of other bridged and heterocyclic analogues are also reported along with their in vitro data. Two compounds showing higher affinity than Gabapentin were selected for evaluation in an animal model of epilepsy. One of these compounds, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexyl)acetic acid hydrochloride (19), was shown to be effective in this model with a profile similar to that of Gabapentin itself.