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We synthesized diaminobutane derivatives as potent Ca(2+)-permeable AMPA receptor antagonists with non-hypotensive activity. Compound 10c showed selective Ca(2+)-permeable AMPA receptor antagonist activity and neuroprotective effects in transient global ischemia models in gerbils.

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In order to obtain non-hypotensive and Ca2+-permeable AMPA receptor antagonists, we have synthesized a series of 1,4-bis(4-piperidinylmethyl)diaminobutanes. Compounds 13b, c, f had desirable properties.

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The effects of nefiracetam [DM-9384; N-(2, 6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide], a cognitive enhancer, on extracellular acetylcholine and glutamic acid in the frontal cortex were studied using brain microdialysis in freely moving rats. Nefiracetam administration (1 mg/kg, p.o.) doubled the amount of acetylcholine in the dialysate. When tetrodotoxin was added to the perfusion solution, the basal level of acetylcholine decreased and nefiracetam caused no increase in acetylcholine outflow. The amount of glutamic acid in the dialysates was not affected by nefiracetam. These results suggest that nefiracetam increases the amount of acetylcholine within the cholinergic synaptic clefts.

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The voltage-dependent block of NMDA channels by Mg2+ is an important functional element of NMDA receptors, since relief of block by depolarization plays a key role in some forms of ischemic neurodegeneration and synaptic plasticity. To identify the relevant structural domains responsible for block by Mg2+ and TCP, we used site-directed mutagenesis to change individual amino acids of the rat NR1A subunit in a transmembrane region (599-DALTLSSAMWFSWGVLLNSGIGE-621, mutated residues underlined) previously shown to donate residues that influence ionic selectivity. Ten mutant NR1A subunits were co-expressed in Xenopus oocytes with either the epsilon 1 or NR2A subunits, and receptor properties were analyzed under two-electrode voltage clamp. The mutation N616R virtually abolished voltage-dependent Mg2+ block, reduced Zn2+ block 5-fold and greatly reduced Ba2+ permeability in confirmation of previous reports. This mutation also reduced the potency of TCP as a use-dependent blocker by 200-fold. The remaining low-affinity TCP block did not appear to be use-dependent, suggesting two blocking sites for TCP. None of the other mutations differed significantly from NR1A itself except S617N, which displayed a 6-fold reduction in Mg2+ block. A well-barrier model of permeation through the NMDA receptor channel is presented that quantitatively reproduces voltage-dependent Mg2+ block. This model demonstrates that only minimum changes energy profiles experienced by permeating ions, equivalent to the energy of a single hydrogen or ionic bond, are required to abolish Mg2+ block. These findings indicate that only small structural changes are needed to convert a Mg(2+)-insensitive ion channel to a channel with pronounced voltage-dependent Mg2+ block.

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Cholinergic innervation of the rat cerebellum was investigated immunohistochemically by using a monoclonal antibody against choline acetyltransferase. Immunoreactive structures included: 1) a subpopulation of mossy fibers and glomerular rosettes; 2) thin varicose fibers, which were closely associated with the Purkinje cell layer and also found in the molecular layer; and 3) relatively dense networks of varicose fibers distributing in the cerebellar nuclei. Quantitative analysis indicated that a great many immunoreactive rosettes were localized in lobules IXc and X, although their density in lobule X was approximately four times that in the lobule IXc. A considerable number of immunoreactive structures were also present in all other lobules. In the hemispheres they were confined to a zone immediately beneath the Purkinje cell layer, whereas in the vermis they were scattered throughout the granular layer. Most of the immunoreactive fibers found in the molecular layer coursed toward the pial surface and were distributed within the inner half of the molecular layer. In the cerebellar nuclei, portions of the medial nucleus and magnocellular portion of the lateral nucleus had moderately dense networks of immunoreactive fibers, whereas loose networks of fibers were observed in the posterior interposed nucleus. Other parts of the cerebellar nuclei contained a smaller number of varicose fibers.

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The effect of ketanserin (KET), a specific 5-hydroxytryptamine2 (5-HT2) receptor blockade, on pressor response to vasoactive substances was examined in rats with one-kidney, one clip renal artery stenosis of 2 days' duration (2-day clipped rat) and in rabbits with renal artery stenosis of 3 days' duration (3-day clipped rabbits). The 2-day clipped rats showed hyperresponsiveness to norepinephrine (NE), arginine vasopressin (AVP) and 5-HT. All hyperresponsiveness were attenuated by a subdepressor dose of KET. The infusion of KET, 10 micrograms/kg/min for 30 minutes, decreased mean arterial pressure of the 3-day clipped rabbits; the dose did not alter blood pressure of the normal controls. Exaggerated pressor response to NE was observed in the 3-day clipped rabbits and was abolished by a subdepressor dose of KET, 2.5 micrograms/kg/min. These results suggest that 5-HT may be involved in the enhanced pressor response to vasoconstrictor substances in the 2-day clipped rats and 3-day clipped rabbits, and that it may also play an important role in maintaining blood pressure in the 3-day clipped rabbits.

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The analgesic effect of cyclazocine microinjected into the diencephalon of rats was studied by using the bradykinin-induced flexor reflex test. The dorsal portion of the medial hypothalamic area was sensitive to cyclazocine with respect to the production of analgesia (ED50 2.6 micrograms/rat). Microinjections of morphine into the same portion also produced a dose-dependent analgesic effect (ED50 2.5 micrograms/rat). As naloxone (0.9 mg/kg s.c.) antagonized both these analgesic effects, the findings suggest that the dorsal portion of the medial hypothalamic area of the rat is one of the primary target sites of analgesic drugs.

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A simple analytical assay method for kyotorphin was developed by the use of amino acid analyzer and the deactivation of kyotorphin in biological media was studied with this method. Kyotorphin was hydrolyzed rapidly by enzymes in serum and brain of rat and mouse, but L-tyrosyl-D-arginine was not. The hydrolysis activity was much higher in brain than in serum. The apparent Michaelis' constants, Km, were of the order of 10(-5) for brain and 10(-4) M for serum in both species. The hydrolysis of kyotorphin was strongly inhibited by bestatin (Ki = 0.1 microM). Thus the hydrolysis might be attributed to aminopeptidase(s). A dose of 50 micrograms of bestatin administered intracisternally potentiated the analgesic activity of kyotorphin by 4.8 times or so. Thus kyotorphin seems to be deactivated by bestatin-sensitive aminopeptidase(s) in brain.

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Muscle relaxant effects of baclofen were compared with those of dantrolene, diazepam, chlordiazepoxide and tolperisone. When administered intraduodenally (i.d.), baclofen and dantrolene but not diazepam suppressed the sustained rigidity of forelimbs in anemically decerebrated rats, and ED50 values of the former two drugs were 2.9 and 22 mg/kg, respectively. Baclofen, dantrolene and diazepam reduced the phasic rigidity of the decerebrated animals induced by mechanical stimulation of hindlimbs, with their respective ED50 values of 6.2, 140 and 1.4 mg/kg, i.d. Both the rigidities were almost insensitive to chlordiazepoxide and tolperisone. With the exception of tolperisone, these drugs also produced a muscle relaxation in intact animals as measured by traction (rats), rotarod (mice), and grip-strength (mice) tests. ED50 or eD25 values were calculated to be in the following ranges: 5.6 approximately 12 mg/kg, p.o. for baclofen, 15 approximately 35 mg/kg, p.o. for dantrolene, 2.1 approximately 6.5 mg/kg, p.o. for diazepam and 33 approximately 64 mg/kg, p.o. for chlordiazepoxide. These results suggest that baclofen, unlike other drugs, may be effective in reducing both tonic and phasic rigidities at lower doses than those causing muscle relaxation in intact animals.

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Cyclazocine (0.5 mg/kg i.v.) inhibited the activity of lamina V-type neurons of the rabbit spinal dorsal horn induced by intra-arterial injection of bradykinin. This inhibition was reversed during temporary spinalization by cold block. Thus, cyclazocine probably depresses nociceptive transmission in the spinal dorsal horn by facilitating descending inhibitory systems which originate from supraspinal structures.

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The effects of a new endogenous opioid dipeptide (Tyr-Arg), kyotorphin, on single unit activities recorded from the lamina V type neurons in the spinal dorsal horn and the neurons in nucleus reticularis paragigantocellularis (NRPG) of the medulla oblongata were investigated in the rabbit and rat, respectively. Microelectrophoretically applied kyotorphin predominantly depressed the lamina V type neurons but excited the NRPG neurons. Such predominant effects were antagonized by naloxone. These results suggest that kyotorphin has qualitatively similar actions to those of enkephalins in both central regions examined.

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Cyclazocine, a benzomorphan derivative, suppressed the flexor reflex of the hind-limb of intact rats induced by intra-arterial injection of bradykinin, a potent pain-producing substance, in a dose-dependent manner, without remarkable influence on motor performance. This suppressive effect was antagonized by naloxone, a specific opiate antagonist. The ED50 values for cyclazocine were 0.054 mg/kg s.c., 5.6 mg/kg p.o., and 1/27, 1/11 of those for pentazocine by the respective routes of administration. In spinal rats, however, the inhibitory effect of cyclazocine and pentazocine on the bradykinin-induced flexor reflex was markedly reduced. Furthermore, cyclazocine as well as pentazocine selectively inhibited the EEG arousal response induced by electrical stimulation of the tooth pulp, which elicits the single sensation of pain. These results indicate that cyclazocine in doses used had a specific analgesic action, and that the main site of action probably is in the supra-spinal structures, such as seen in the case of pentazocine.

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