Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.

Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.

Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration.

Prolonged or high-intensity exposure to visible light leads to photoreceptor cell death. In this study, we demonstrate a novel pathway of light-induced photoreceptor apoptosis involving the low-affinity neurotrophin receptor p75 (p75NTR). Retinal degeneration upregulated both p75NTR and the high-affinity neurotrophin receptor TrkC in different parts of Müller glial cells. Exogenous neurotrophin-3 (NT-3) increased, but nerve growth factor (NGF) decreased basic fibroblast growth factor (bFGF) production in Müller cells, which can directly rescue photoreceptor apoptosis. Blockade of p75NTR prevented bFGF reduction and resulted in both structural and functional photoreceptor survival in vivo. Furthermore, the absence of p75NTR significantly prevented light-induced photoreceptor apoptosis. These observations implicate glial cells in the determination of neural cell survival, and suggest functional glial-neuronal cell interactions as new therapeutic targets for neurodegeneration.

Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells.

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.

Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy.

A 48-year-old man without underlying disease developed mediastinitis and was treated by mediastinal drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in a culture of the abscess material. He was treated with anti-MRSA antibiotics and the MRSA infection improved. Four weeks after the onset of MRSA infection, he developed rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome (NS). A renal biopsy showed endocapillary proliferative glomerulonephritis with IgA-predominant glomerular deposition. These clinicopathological findings were consistent with those in glomerulonephritis following MRSA infection (post-MRSA infection glomerulonephritis). The level of serum creatinine increased to 6.3 mg/dl, 7 weeks after the onset of RPGN. At that time, the eradication of MRSA infection was considered. He was given middle-dose steroid therapy. Thereafter, his RPGN with NS improved. MRSA infection did not recur. If the disease activity of post-MRSA infection glomerulonephritis persists after the disappearance of MRSA infection, the application of immunosuppressive therapy with steroids may be useful.

Auraptene in the Peels of Citrus Kawachiensis (Kawachibankan) Contributes to the Preservation of Cognitive Function: A Randomized, Placebo-Controlled, Double-Blind Study in Healthy Volunteers.

OBJECTIVES: Dementia, which is characterized by a progressive decline in cognitive function, is a major concern in aging societies. Although a number of treatments have been approved, an effective therapy to prevent the disorder is lacking. A supplement that improves cognitive function would benefit patients. The aim of this study was to assess whether auraptene, a citrus coumarin, has a protective effect on cognitive decline. DESIGN: A randomized, placebo-controlled, double-blind study SETTING: Outpatient medical check-up program for cognitive disorders PARTICIPANTS: 84 adult volunteers (they are cognitively normal) met inclusion and exclusion criteria to participate. INTERVENTION: 42 participants received auraptene enriched (containing 6.0 mg/day of auraptene) test juice, and another participants received placebo juice. MEASUREMENTS: 1) Mild Cognitive Impairment (MCI) Screen using the 10-word immediate recall test. 2) The Mini-Mental State Examination (MMSE). Cognitive assessment ware carried out baseline and at 24 weeks. RESULTS: Auraptene enriched test juice did not improve cognitive function after 24 weeks compared with baseline data. However, there was a significant difference in the percentage change in cognitive function between the test and placebo orange juice groups (6.3 ± 18.9 vs. -2.4 ± 14.8, P < 0.05). Multiple regression analysis demonstrated a significant independent relationship between the percentage change in the 10-word immediate recall test score and test juice consumption including baseline 10-word immediate recall test score in all subjects. CONCLUSION: This is the first study to assess the effectiveness of auraptene in the prevention of cognitive decline. Our results suggest that auraptene is a safe supplement for the prevention of cognitive decline.

Focal segmental glomerulosclerosis associated with polycythemia vera: report of a case and review of the literature.

A 69-year-old female with a 3-year history of polycythemia vera (PV) developed nephrotic syndrome. A renal biopsy showed focal and segmental glomerulosclerosis (FSGS). The patient was treated with prednisolone and myelosuppressive agents. Thereafter, parallel improvement of the two conditions was observed. After 4-year treatment, proteinuria disappeared. To our knowledge, there are five reported cases of FSGS associated with PV. Among them, three patients suffered from progressive azotemia. We suggest that steroid therapy with myelosuppressive agents can resolve the renal lesion in patients with PV.

A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer.

The human embryonal carcinoma cells NEC14 can be induced to differentiate morphologically by the addition of 10(-2) M N, N'-hexamethylene-bis-acetamide and cease to grow in several days. Transcription factors of the E2F/DP family have been shown to be closely related to the regulation of cell proliferation. To analyse cellular proteins which interact with E2F in NEC14 cells, cDNA clones encoding E2F binding proteins were isolated from a lambdaZAP II NEC14 cell library with the 32P-labeled GST (Glutathione S-transferase)-E2F-1 fusion protein as a probe. One of the clones encodes E2FBP1 which has the helix-loop-helix (HLH) motif, but lacks the basic domain and the zipper structure usually found at N- and C-terminal sides to the HLH motif, respectively. The arrangement of amino acids in the helix 1 and helix 2 regions is quite similar to those of Mxi and Mad, but different from those of E2F-1 and DP-1. Western blot analysis of the immunoprecipitates prepared with anti-E2FBP1 antibody showed that E2FBP1 associates with both E2F-1 and DP-1 in vivo. E2FBP1 alone has no DNA binding activity, but bind to the E2F site through heterodimerization with E2F-1 but not with DP-1. Although E2FBP1 lacks the transactivation domain, it stimulates E2F site-dependent transcription in cooperation with E2F-1.

Phencyclidine alters regional concentrations of neuropeptide Y and peptide YY in rat brain.

The psychotomimetic effects of Phencyclidine (PCP) often have a delayed onset and extend far from the time plasma drug levels reach their peak. PCP at a low dose is considered selective for actions on the N-methyl-D-aspartate-PCP receptor. We evaluated effects of PCP (2 and 10 mg/kg, IP) on regional content of neuropeptide Y (NPY)-like immunoreactivity (LI) and peptide YY (PYY)-LI, in the rat brain. Thirty minutes after administration of PCP, NPY-LI levels were significantly elevated in some limbic structures following both doses. A significant, widespread increase in NPY-LI levels was induced 2 hours after administration of the higher dose of PCP. On the contrary, NPY-LI was significantly decreased in a number of the regions 24 hours after PCP. The extent of reduction was less following the higher dose of PCP than following the lower dose. PCP did not cause a consistent effect on PYY-LI. The findings suggest that effects of PCP on brain NPY content might depend on the dose and the interval between administration of the drug and sacrifice.

The world of archaea: genome analysis, evolution and thermostable enzymes.

Pyrococcus sp. KOD1 is a newly isolated hyperthermophilic archaeon from a solfatara at a wharf on Kodakara Island, Kagoshima, Japan. A physical map of the KOD1 chromosome was constructed using pulsed-field gel electrophoresis of restriction fragments generated by AscI, PacI and PmeI. The order of the AscI fragments was deduced from Southern hybridization using the AscI, PmeI and PacI fragments as a probe. The derived physical map indicates that KOD1 possesses a circular-form genome and its size was estimated to be 2036 kb. Several cloned genes were hybridized to restriction fragments to locate their positions on the physical map. Some genes involved in the central dogma were located on the restricted segment of the genome. Novel characteristics of KOD1 enzymes are also introduced in this article.

Amino acid residues in the transmembrane domain of the type 1 sigma receptor critical for ligand binding.

The type 1 sigma receptor expressed in Xenopus oocytes showed binding abilities for the sigma-1 ligands, [3H](+)pentazocine and [3H]NE-100, with similar kinetic properties as observed in native tissue membranes. Amino acid substitutions (Ser99Ala, Tyr103Phe and di-Leu105,106di-Ala) in the transmembrane domain did not alter the expression levels of the type 1 sigma receptor as determined by immunoblot analysis using an anti-type 1 sigma receptor antiserum. By contrast, ligand binding was significantly suppressed by the substitutions. These findings provide evidence that the transmembrane domain of the type 1 sigma receptor plays a critical role in ligand binding of this receptor.

Effect of minaprine on synaptic transmission in the neocortex of the rat in vivo.

The effects of minaprine and/or excitatory amino acid antagonists on transcallosal responses were examined in urethane-anesthetized rats. The transcallosal response was recorded from the surface of the anterior neocortex, following electrical stimulation of the contralateral corpus callosum. The transcallosal response consisted of a biphasic positive-negative waveform. Intravenously-administered minaprine increased the amplitude of the positive- and negative-waves, in a dose-dependent manner. Intracortical injection of (+/-)-2-amino-5-phosphonovalerate (APV) and gamma-D-glutamylglycine (DGG) reduced the amplitude of the negative-wave, with no effects on the amplitude of the positive-wave. L-Glutamate diethylester (GDEE) had no effect on the transcallosal response. The minaprine-induced increase in the amplitude of the negative-wave was completely antagonized by simultaneous intracortical injections of APV and DGG which, per se, did not affect that transcallosal response. In contrast, APV and DGG had no effect on the increase in the amplitude of the positive-wave induced by minaprine. The enhancing effect of minaprine on the transcallosal response remained unaltered in case of an intracortical injection of GDEE. These findings indicate that the negative-wave of the transcallosal response may be related to receptors for excitatory amino acids. The possibility that the pharmacological action of minaprine on synaptic transmission in the neocortex may be linked to the excitatory amino acid receptors warrants further attention.

Action of nootropic drugs on transcallosal responses in rats.

The effects of nootropic drugs and related compounds on transcallosal responses were examined in urethane-anesthetized rats. The transcallosal response was recorded from the surface of the anterior neocortex following electrical stimulation of the contralateral corpus callosum. The transcallosal response consisted of a biphasic positive-negative waveform. Hopantenate increased the amplitude of the positive- and negative-waves, without affecting the latency. Aniracetam, idebenone, bifemelane hydrochloride, TRH and meclofenoxate increased the amplitude of the negative-wave, without affecting the latencies. Vinpocetine and eburunamonine had no effect on the transcallosal response. Muscimol, amino-oxyacetic acid, diazepam and pentobarbital increased the amplitude of the positive-wave and decreased the amplitude of the negative-wave, without affecting the latencies. Bicuculline and picrotoxin increased the amplitude of the negative-wave, without affecting the latencies. Physostigmine decreased the amplitude of the negative-wave, without affecting the latency. Atropine was without effect. The pharmacological nature of the transcallosal response is discussed, based on findings with 16 different pharmacological agents.

Effects of apomorphine and (+/-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine, injected into the striatum, on the caudate spindle in the rat.

The caudate spindle in rats was observed following bilateral application of apomorphine (1.5-50 micrograms) and (+/-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 0.3-3 micrograms) into the striatum. The smallest dose (1.5 micrograms) of apomorphine enhanced the spindle whereas with a larger dose (50 micrograms), suppression occurred. The preferential dopamine (DA) autoreceptor (inhibitory-receptor) agonist, (+/-)-3-PPP, enhanced the spindle, in a dose-dependent manner. The enhancing effect of apomorphine (1.5 micrograms) and (+/-)-3-PPP (3 micrograms) was prevented by neuroleptics, such as haloperidol (20 micrograms/kg, i.v.) and sulpiride (2 mg/kg, i.v.) at doses which, per se, did not affect the spindle. Small doses of neuroleptics are thought to block DA autoreceptors, suggesting that the enhancing effects of the DA agonists are mediated by autoreceptors. These results lend further support to the assumption that the development of the caudate spindle involves activation or DA receptors. Enhancement of the spindle, induced by injections of apomorphine into the striatum (small dose) and (+/-)-3-PPP, may be mediated by DA autoreceptors (inhibitory-receptors) located at presynaptic elements of the nigro-striatal DA system, while suppression may be due to stimulation of the postsynaptic DA receptors.

Behavioral evidence for modulation by sigma ligands of (+)MK-801-induced hyperlocomotion in monoamine-depleted mice.

The selective non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo(a, d)cyclohepten-5,10-imine maleate ((+)MK-801) led to a dose-dependent increase in locomotor activity in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine (alpha-MT). A selective and potent sigma receptor "antagonist" NE-100 (N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride), which did not per se affect spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. Sulpiride, a dopamine D2 receptor antagonist, and clozapine, a dopamine D4 receptor antagonist, which decreased spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. The sigma receptor "agonists" (+)N-allynormetazocine [(+)SKF10,047], (+)pentazocine and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP], which did not per se affect spontaneous locomotor activity, did dose-dependently enhance the hyperlocomotion induced by (+)MK-801. The enhancement of (+)MK-801-induced the hyperlocomotion by (+)SKF10,047, (+)pentazocine and (+)3-PPP was completely blocked by NE-100. The enhancement of (+)MK-801-induced hyperlocomotion by (+)pentazocine was not affected by treatment with sulpiride and clozapine. As sigma ligands can markedly attenuate NMDA antagonist-induced behavior, the major physiological role of sigma receptors in vivo might be to modulate functions of the NMDA receptor ion channel complex.

In vivo receptor occupancy of NRA0045, a putative atypical antipsychotic, in rats.

We have previously reported that (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045) is a novel antipsychotic agent with affinities for dopamine D4, 5-hydroxytryptamine 2A (5-HT2A) and alpha1 receptors. In the present study, in vivo receptor occupancy of 5-HT2A, alpha1, dopamine D2 and D3 receptors by NRA0045 was assessed, based on in vivo and ex vivo receptor binding, and findings were compared to reference antipsychotic drugs (haloperidol, risperidone, clozapine). Intraperitoneal administration of haloperidol highly occupied the dopamine D2 receptor in the striatum and nucleus accumbens, and alpha1 adrenoceptors in the frontal cortex. Occupation of the 5-HT2A receptor in the frontal cortex and the dopamine D3 receptor in the nucleus accumbens and islands of Cajella was moderate. By contrast, atypical antipsychotics such as risperidone and clozapine dose-dependently occupied the 5-HT2A receptor in the frontal cortex, with moderate to negligible occupancy of the D2 receptor in the striatum and the nucleus accumbens. Clozapine and risperidone also occupied the alpha1 adrenoceptor in the frontal cortex, and clozapine did not occupy the dopamine D3 receptor. As seen with other atypical antipsychotics, intraperitoneal administration of NRA0045 dose-dependently occupied the 5-HT2A receptor and the alpha1 adrenoceptor in the frontal cortex, while it was without effect on dopamine D2 and D3 receptors in the striatum, nucleus accumbens and islands of Cajella. Thus, the strong occupancy of 5-HT2A and alpha1 receptors is involved in the pharmacological action of NRA0045.

Structure-activity studies of 4,6-disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives with analgesic and antiinflammatory activities.

4,6-Disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives showed analgesic and antiinflammatory activities when assayed by the acetic acid writhing test in mice and the carrageenin edema test in rats. To understand how the substituents affect the biological activities, the quantitative structure-activity relationships (QSAR) of 38 compounds were analyzed using the adaptive least-squares method (ALS method). The resulting QSAR suggested that some chemical modifications of 4,6-disubstituted furo[3,2-b]indole derivatives would improve their biological activities. Thus, 15 additional compounds were synthesized to reinforce and confirm the correlation. Among these compounds, particularly 4-(2-ethylhexanoyl)-2-(morpholinocarbonyl)-6-(trifluoromethy l) furo[3,2-b]indole showed pronounced biological activities. This compound gave a pharmacological activity spectrum similar to that of tiaramide but exhibited much higher potency.

Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs.

sigma Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy-6H-dibenzo[b,d]pyran hydrochloride 2a had selective affinity for sigma receptor over dopamine D2 receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the evidence, N, N-dipropyl-2-(4-methoxy-3-benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for sigma receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3.

Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover sigma(1) ligands.

The synthesis and structure-activity relationships (SAR) of 1-alkyl-2-phenylethylamine derivatives 5-8 designed from N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (1, NE-100) are presented. The SAR between compound 1 and 1-alkyl-2-phenylethylamine derivatives suggested that the alkyl group on the 1-position carbon of 2-[4-methoxy-3-(2-phenylethyl)phenyl]ethylamine derivatives played the role of one of the propyl groups on the aminic nitrogen of compound 1. (-)-N-Propyl-1-butyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylam ine hydrochloride ((-)-6d, NE-537) and (-)-N-propyl-1-(3-methybutyl)-2-[4-methoxy-3-(2-phenylethoxy )phenyl]e thylamine hydrochloride ((-)-6i, NE-535), typical compounds in this series, have potent and selective sigma(1) affinity.

Synthesis and pharmacological evaluation of (nitrooxy)alkyl apovincaminates.

A series of (nitrooxy)alkyl apovincaminates has been synthesized and evaluated for their effects on vertebral and femoral blood flow. These derivatives were prepared from apovincaminic acid (4). In cerebral circulation, compound 5 (0.03-1.0 mg/kg iv) caused a dose-dependent increase in cerebral blood flow (CerBF) without affecting the blood pressure. It was more potent than vinpocetine (2). The structures of 2 and 5, determined by X-ray crystallography, showed differences in the electrostatic potential image and in the conformation of the ethyl group at the 16-position.

Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists.

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.