piperidines and 1-(1-3-benzodioxol-5-ylcarbonyl)piperidine

The current study was designed to investigate the effects of 1-(1,3-benzodioxol-5-yl-carbonyl) piperidine (1-BCP) on swimming endurance capacity which as one indicator of fatigue in the weight-loaded forced swimming mice. Mice were given either vehicle or 1-BCP (0.1, or 0.2 mmol/kg body weight daily) by intraperitoneal injection once daily for 2 weeks. The 1-BCP groups showed a significant increase in swimming time to exhaustion compared with the control group. 1-BCP increased the liver glycogen (LG) and muscle glycogen (MG) contents significantly, while decreased the lactic acid (LA) and blood urea nitrogen (BUN) levels notably compared with control group. Besides, 1-BCP treatment also significantly improved the endogenous cellular antioxidant enzymes in mice by increasing the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Therefore, this study demonstrated for the first time that the supplementation of 1-BCP, as a positive allosteric modulator of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, could enhance the endurance capacity of mice and facilitated them recovery from fatigue. Thus, we provide a new effective therapeutic strategy for fatigue.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antioxidants; Blood Urea Nitrogen; Catalase; Dietary Supplements; Dioxoles; Fatigue; Glutathione Peroxidase; Glycogen; Lactic Acid; Liver; Male; Mice; Mice, Inbred Strains; Muscle, Skeletal; Physical Endurance; Piperidines; Receptors, AMPA; Superoxide Dismutase; Swimming

To explore novel antifatigue agents targeting with AMPA receptor, 10 compounds were synthesized and their structures were confirmed by 1H NMR, ESI-MS and elemental analysis. 1-BCP was treated as the leading compound. The antifatigue activities were evaluated by weight-loaded forced swimming test, and the AMPA receptor binding affinities were tested with radioligand receptor binding assays. The results unveiled that 5b appeared to possess potent antifatigue activities and high affinity with AMPA receptor, which deserved further studies.

Topics: Animals; Benzamides; Dioxoles; Fatigue; Piperidines; Radioligand Assay; Receptors, AMPA; Swimming

Pyrilamine, a selective histamine H(1) antagonist, impaired spatial memory, and decreased hippocampal theta activity during a radial maze task.. We investigated the ameliorative effects of glutamatergic drugs on pyrilamine-induced spatial memory deficit and the decrease in hippocampal theta activity in rats.. Drug effects were measured using an eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was also recorded with a polygraph system using a telemetric technique.. Intraperitoneal injection of pyrilamine (35 mg/kg) resulted in impaired reference and working memory in the radial maze task and a decrease in the amplitude and power of hippocampal theta waves. The working memory deficit and the decrease in hippocampal theta power were antagonized by intrahippocampal injection of D: -cycloserine (1 microg/side), spermidine (10 microg/side), spermine (10 microg/side), aniracetam (1 microg/side), and 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine (1-BCP) (1 microg/side), but not concanavalin A.. These results clearly indicate that H(1) antagonist-induced working memory deficit, and the decrease in hippocampal theta activity was closely associated with hippocampal glutamatergic neurotransmission mediated by N-methyl-D: -aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Topics: Animals; Concanavalin A; Cycloserine; Dioxoles; Dose-Response Relationship, Drug; Electroencephalography; Fourier Analysis; GluK2 Kainate Receptor; Hippocampus; Histamine H1 Antagonists; Injections; Male; Maze Learning; Mental Recall; Orientation; Piperidines; Pyrilamine; Pyrrolidinones; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Histamine H1; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Signal Processing, Computer-Assisted; Spermidine; Spermine; Theta Rhythm

Ampakines are small benzamide compounds that allosterically produce the positive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) was investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers. The drug increased the open time of AMPA-induced single channel current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the modulated currents were blocked by CNQX. It is concluded that the synaptic membrane environment is not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. They also raise the possibility that AMPA receptors are regulated by factors present in situ, thus explaining the more efficient modulatory effects of CX509 when acting on receptors removed from their synaptic location.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzamides; Brain; Dioxoles; Excitatory Amino Acid Agonists; Ion Channels; Memory; Neurons; Nootropic Agents; Piperidines; Pyridines; Pyrrolidinones; Rats; Receptors, AMPA; Subcellular Fractions; Synaptic Membranes; Time Factors

Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.

Topics: Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cerebral Cortex; Dioxoles; Dose-Response Relationship, Drug; Electric Stimulation; Hippocampus; Male; Piperidines; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, AMPA

The effects of various (S)-alpha-amino-3-hydroxy-5-methyl-4-izoxazole-propionate (AMPA) receptor modulators on AMPA-induced whole-cell currents were compared in isolated rat cerebellar Purkinje cells. The positive modulators, aniracetam, cyclothiazide, 1-(1, 3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and 1-(quinoxaline-6-ylcarbonyl)-piperidine (BDP-12), dose-dependently potentiated the steady-state component of AMPA currents. The negative modulator, (-)1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI 53784), dose-dependently suppressed AMPA responses. Its concentration-response curve was shifted to the right in a parallel fashion by all positive modulators, indicating a competitive type of interaction. However, the relative potencies of the positive modulators were different with regard to the enhancement of AMPA responses and the reversal of GYKI 53784-induced inhibition, respectively. It is supposed that positive modulators act at multiple allosteric sites and that they interact with GYKI 53784 at only one of these sites.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzodiazepines; Benzothiadiazines; Cells, Cultured; Cerebellum; Dioxoles; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Membrane Potentials; Piperidines; Purkinje Cells; Pyrrolidinones; Rats; Receptors, AMPA

Aniracetam, 1-(1,3-benzodioxol-5-yl-carbonyl)piperidine (1-BCP) and cyclothiazide, three compounds considered to enhance cognition through modulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, were evaluated in the 'kynurenate test', a biochemical assay in which some nootropics have been shown to prevent the antagonism by kynurenic acid of the N-methyl-D-aspartate (NMDA)-evoked [3H]noradrenaline ([3H]NA) release from rat hippocampal slices. Aniracetam attenuated the kynurenate (100 microM) antagonism of the [3H]NA release elicited by 100 microM NMDA with high potency (EC50< or =0.1 microM). Cyclothiazide and 1-BCP were about 10 and 100 times less potent than aniracetam, respectively. The effect of aniracetam persisted in the presence of the AMPA receptor antagonist 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) added at 5 microM, a concentration that did not affect NMDA receptors; in contrast, NBQX reduced the effect of 1-BCP and abolished that of cyclothiazide. The AMPA-evoked release of [3H]NA from hippocampal slices or synaptosomes was enhanced by cyclothiazide, less potently by 1-BCP and weakly by aniracetam. High concentrations of kynurenate (1 mM) antagonized the AMPA-evoked [3H]NA release in slices; this antagonism was attenuated by 1 microM cyclothiazide and reversed to an enhancement of AMPA-evoked [3H]NA release by 10 microM of the drug, but was insensitive to 1-BCP or aniracetam. It is concluded that aniracetam exerts a dual effect on glutamatergic transmission: modulation of NMDA receptor function at nanomolar concentrations, and modulation of AMPA receptors at high micromolar concentrations. As to cyclothiazide and 1-BCP, our data concur with the idea that both compounds largely act through AMPA receptors, although an NMDA component may be involved in the effect of 1-BCP.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antihypertensive Agents; Benzothiadiazines; Dioxoles; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Heterocyclic Compounds; Hippocampus; In Vitro Techniques; Kynurenic Acid; Male; N-Methylaspartate; Nootropic Agents; Norepinephrine; Piperidines; Pyrrolidinones; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Tritium

The benzoylpiperidine 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and related compounds, potentiate alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acidergic (AMPAergic) synaptic currents in central neurons, and improve performance of rodents and humans on learning and memory tasks. Their physiological actions are similar but not identical to thiazides, which also enhance AMPAergic synaptic responses and improve performance of rats in water-maze and passive-avoidance tests. Thiazides also dramatically increase AMPA receptor-mediated neuronal death in vitro and in vivo. Here it was evaluated whether 1-BCP potentiated AMPA receptor-mediated excitotoxicity in hippocampal neuron cultures. Glutamate + MK 801 (to block NMDA receptors) + 1 mM 1-BCP produced neuronal death that was reversed by 10 microM 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX), a selective AMPA receptor antagonist. 1-BCP and drugs with similar activities can facilitate AMPA receptor-mediated excitotoxicity.

Topics: Animals; Benzothiadiazines; Cell Survival; Cells, Cultured; Dioxoles; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Neurons; Neurotoxins; Piperidines; Quinoxalines; Rats; Receptors, AMPA

Two allosteric alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive modulators, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine (1-BCP) and 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516), and the antipsychotic drug, haloperidol, were tested for their ability to inhibit hyperactivity induced by amphetamine and dizocilpine in mice. Haloperidol (0.03-1.0 mg/kg) and 1-BCP (20.0-120.0 mg/kg) attenuated hyperactivity induced by both amphetamine and dizocilpine, with higher potency against amphetamine. CX516 (30.0-170.0 mg/kg), however, failed to attenuate amphetamine- and dizocilpine-induced hyperactivity up to a dose which decreased spontaneous locomotor activity. These results indicate that AMPA receptor positive modulators may not be uniform with regard to their effects on dopamine-mediated behaviors and their antipsychotic potential.

Topics: Amphetamine; Animals; Antipsychotic Agents; Central Nervous System Stimulants; Dioxoles; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Haloperidol; Locomotion; Male; Mice; Piperidines; Receptors, AMPA

It is now clear that the AMPA subtype of ionotropic glutamate receptors (iGluRs) undergoes a rapid desensitization in response to activation by AMPA receptor agonists. This desensitization is inhibited by compounds such as aniracetam and cyclothiazide, which act at a distinct site on the AMPA receptor complex. In particular, cyclothiazide greatly potentiates AMPA receptor-mediated depolarizing responses in the hippocampus. We have recently shown cyclothiazide also increases AMPA-induced release of [3H]norepinephrine ([3H]NE). More, recently, a benzamide compound, 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), has been reported to enhance AMPA-induced currents and to facilitate memory retention in rats in a number of memory tasks. In this study, the effects of 1-BCP on excitatory amino acid agonist-induced [3H]NE release in rat hippocampal slices were determined. We report that 1-BCP, like cyclothiazide, selectively potentiates AMPA-induced [3H]NE release. However, cyclothiazide was more potent and efficacious than 1-BCP. Nevertheless, these data suggest a role for AMPA receptor-mediated enhancement of norepinephrine release as a mechanism of action for nootropic compounds such as 1-BCP.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzothiadiazines; Dioxoles; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; Memory; N-Methylaspartate; Norepinephrine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA

Centrally active drugs that enhance alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-gated currents by increasing the amplitude and duration of fast, excitatory synaptic responses in the hippocampus have recently been described. The effects of the compound 1-(1,3-benzodioxol-5-ylcarbonyl) perperidine (BDP) on associative and non-associative aspects of the classically conditioned eyeblink response in the freely moving rat were examined. Rats injected with BDP blinked significantly more to an acoustic stimulus of 85 dB than did vehicle controls, indicating that the drug enhances alpha responding to discrete auditory cues. Using a less intense stimulus of 80 dB, rats injected with BDP did not exhibit alpha responding or pseudo-conditioning, yet learned the conditioned response at a facilitated rate. These results suggest that increasing excitatory neurotransmission enhances the processing of sensory information and may contribute to subsequent contingency detection.

Topics: Acoustic Stimulation; Animals; Arousal; Blinking; Conditioning, Classical; Cues; Dioxoles; Excitatory Amino Acid Agonists; Glutamic Acid; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Sensory Receptor Cells; Synaptic Transmission

Systemic administration of the drug 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP) has been reported to enhance monosynaptic responses in the hippocampus in vivo and to improve spatial and olfactory memory in rats. The drug's mechanism of action was investigated in the present study using membrane patches excised from cultured hippocampal slices. The decay time of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor mediated inward currents was greatly increased by 1-BCP in a concentration dependent and reversible fashion; peak current was also enhanced but to a lesser degree. In vitro slice experiments indicated that the drug has parallel effects on the field EPSP. It is concluded that 1-BCP is a centrally active modulator of the AMPA receptor.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dioxoles; Dose-Response Relationship, Drug; Evoked Potentials; Glutamates; Glutamic Acid; Hippocampus; Membrane Potentials; Organ Culture Techniques; Piperidines; Pyramidal Cells; Quinoxalines; Rats; Receptors, AMPA

An experimental drug, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine, that facilitates glutamatergic transmission in brain after systemic administration was tested for its effects on the induction of long-term potentiation in the hippocampus of rats. Intraperitoneal injections of the drug markedly increased the degree and duration of long-term potentiation; similar results were obtained with an analogue of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine that was also found to improve retention of memory in a radial maze task and in an odor-matching problem. These results define tools for enhancing long-term potentiation in vivo and confirm an important prediction from the hypothesis that long-term potentiation is a substrate of memory.

Topics: Animals; Blood-Brain Barrier; Dioxoles; Excitatory Amino Acid Agonists; Glutamates; Long-Term Potentiation; Piperidines; Rats; Synaptic Transmission; Tissue Distribution; Tomography, Emission-Computed

A benzamide drug that crosses the blood-brain barrier and facilitates DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses was tested for its effects on memory in three behavioral tasks. The compound reversibly increased the amplitude and prolonged the duration of field excitatory postsynaptic potentials in hippocampal slices and produced comparable effects in the dentgate gyrus in situ after intraperitoneal injections. Rats injected with the drug 30 min prior to being given a suboptimal number of training trials in a two-odor discrimination task were more likely than controls to select the correct odor in a retention test carried out 96 hr later. Evidence for improved memory was also obtained in a water maze task in which rats were given only four trials to find a submerged platform in the presence of spatial cues; animals injected with the drug 30 min before the training session were significantly faster than vehicle-injected controls in returning to the platform location when tested 24 hr after training. Finally, the drug produced positive effects in a radial maze test of short-term memory. Well trained rats were allowed to retrieve rewards from four arms of an eight-arm maze and then tested for reentry errors 8 hr later. The number of such errors was substantially reduced on days in which the animals were injected with the drug before initial learning. These results indicate that a drug that facilitates glutamatergic transmission enhances the encoding of memory across tasks involving different sensory cues and performance requirements. This may reflect an action on the cellular mechanisms responsible for producing synaptic changes since facilitation of AMPA receptors promotes the induction of the long-term potentiation effect.

Topics: Animals; Behavior, Animal; Dioxoles; Hippocampus; In Vitro Techniques; Learning; Long-Term Potentiation; Male; Memory; Piperidines; Rats; Receptors, AMPA; Receptors, Glutamate; Synaptic Transmission; Time Factors

A recently developed benzamide compound which facilitates glutamate receptor-mediated synaptic responses was used to test behavioral consequences of enhanced glutamatergic transmission. The drug was found to depress exploratory activity by rats in a novel environment. At a dose below threshold for causing such effects, drug-treated and control rats exhibited no evident behavioral differences during the acquisition phase of a radial maze experiment. Yet, when tested 2.5 h later, experimental animals were more likely than controls to choose maze arms that had not been entered during the acquisition session, suggesting that the drug enhanced retention of information about prior choices and the maze environment.

Topics: Animals; Behavior, Animal; Benzamides; Dioxoles; Electrophysiology; Exploratory Behavior; Glutamine; Hippocampus; Learning; Male; Piperidines; Rats; Synaptic Transmission