piperidines and 2-amino-3-phosphonopropionic-acid

The glucose deprivation-induced release of [3H]D-aspartate was studied in bovine and human retinas in a superfusion apparatus. [3H]D-aspartate release was significantly increased upon omitting glucose in the superfusion buffer. This effect was dependent on external Ca2+ because L- and N-type Ca2+-channel blockers, such as diltiazem (1 microM), nitrendipine (1 microM), and omega-conotoxin (100 nM), significantly reduced the effect of glucose-deprivation induced release of [3H]D-aspartate. Furthermore, while glutamate receptor agonists (L-glutamate, N-methyl-D-aspartate, but not kainate) potentiated the effects of glucose deprivation, antagonists (MK-801, MCPG, ifenprodil, and L-AP3) at these receptors blocked the glucose deprivation-induced release process. Taken together, these studies have demonstrated that under conditions of glucose deprivation, as may happen during ischemic events in vivo, the retinal glutamatergic nerve endings and/or glial cells promote the efflux of [3H]D-aspartate into the extracellular environment. This process appears to be receptor-mediated and dependent on extracellular Ca2+ and is similar to previous reports pertaining to brain tissues.

Topics: Alanine; Animals; Biguanides; Calcium Channel Blockers; Cattle; D-Aspartic Acid; Diltiazem; Dizocilpine Maleate; Drug Synergism; Glucose; Glutamic Acid; Glycine; Humans; Kainic Acid; N-Methylaspartate; Nitrendipine; omega-Conotoxins; Perfusion; Piperidines; Polyamines; Receptors, Glutamate; Retina; Tritium; Verapamil

Recent research has focused on prostaglandins in the central nervous system and their contribution to hyperalgesia and allodynia. This study sought to establish whether neurokinin-1 (NK-1) receptors and glutamate receptors are involved in the hyperalgesic and allodynic effects of spinally administered prostaglandin E2 (PGE2) in rats, and also to determine if the same receptors are involved the hyperalgesia induced by intraplantar administration of zymosan, an inflammatory agent which is known to evoke spinal PGE2 release. Spinal application of antagonists of the NK-1 receptor, the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate or metabotropic glutamate receptor significantly attenuated the decrease in mechanical paw withdrawal response thresholds produced by either spinal administration of PGE2 or intraplantar administration of zymosan. The decrease in thermal paw withdrawal response latencies induced by PGE2, but not by zymosan, was significantly attenuated by spinal administration of an N-methyl--aspartate (NMDA) receptor antagonist, an AMPA/kainate receptor antagonist, or a metabotropic glutamate receptor antagonist. Allodynia induced by PGE2 was significantly alleviated by antagonists of NMDA or AMPA/kainate receptors. These results suggest that both PGE2-induced and zymosan-induced mechanical hyperalgesia are mediated in part through activation of NK-1, AMPA/kainate and metabotropic glutamate receptors. PGE2-induced, but not zymosan-induced, thermal hyperalgesia is mediated in part by activation of NMDA, AMPA/kainate and metabotropic glutamate receptors. Activation of both NMDA and AMPA/kainate receptors contribute to PGE2-induced allodynia.

Topics: 2-Amino-5-phosphonovalerate; Alanine; Animals; Dinoprostone; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinoxalines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Neurokinin-1; Spinal Cord; Zymosan

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Alanine; Animals; Cell Survival; Cells, Cultured; Chick Embryo; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Methylmalonic Acid; Neurons; Neuroprotective Agents; Neurotoxins; NG-Nitroarginine Methyl Ester; Piperidines

The receptor mechanisms by which the selective cannabinoid CB1 receptor antagonist/inverse agonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyraz ole-carboxamide] produces scratching and head-twitch response (HTR) in naive mice were examined. Acute intraperitoneal administration of varying doses of SR 141716A produced both scratchings (ED50 = 3.9 mg/kg) and head-twitches (ED50 = 4.6 mg/kg) in a dose-dependent manner. A dose of 10 mg/kg SR 141716A was used to induce the cited behaviors for drug interaction studies. The selective 5-HT2A/C receptor antagonist, SR 46349B [trans-4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3-(2-fluorophenyl) propen-1-yl] phenol] potently and completely blocked the head-twitches produced by SR 141716A (ID50 = 0.08 mg/kg). The induced scratching behavior was partially (68%) and less potently (ID50 = 0.6 mg/kg) blocked by SR 46349B pretreatment. The AMPA/kainate receptor antagonist, CNQX [6-cyano-7-nitroquinoxaline-2,3-dione], partially attenuated (68-78%) the induced scratching and head-twitching behaviors. On the contrary, the selective NMDA antagonist, AP-3 [(+/-)-2-amino-3-phosphonopropionic acid], had no significant effect on these behaviors. The selective tachykinin NK1 antagonist, CP 94, 994 [(+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], also partially attenuated both the scratching (64%) and the head-twitching (76%) symptoms produced by SR 141716A. Since SR 141716A lacks affinity for the discussed receptors, it appears that the induction of the cited behaviors probably involve indirect activation of their respective neurotransmitter systems.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Alanine; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Dronabinol; Excitatory Amino Acid Antagonists; Fluorobenzenes; Glutamic Acid; Head Movements; Injections, Intraperitoneal; Male; Mice; Mice, Inbred ICR; Neurotransmitter Agents; Phenols; Piperidines; Psychotropic Drugs; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Serotonin; Serotonin Antagonists; Tachykinins

The effect of a novel cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) on cAMP formation was investigated in both slices and membranes of the rat cerebral cortex. NS-105 (10(-8)-10(-6) M) inhibited forskolin-stimulated cAMP formation in membranes, however, the compound significantly enhanced the cAMP formation in pertussis toxin-pre-treated membranes, an action that was abolished by cholera toxin. In contrast, in digitonin-permeabilized membranes, NS-105 had no influence on Mn2+-stimulated cAMP formation. Both of the inhibitory and facilitatory actions of NS-105 on cAMP formation were mimicked by a metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and an adrenergic alpha2 agonist UK-14,304, and blocked by a mGluR antagonist 2-amino-3-phosphonopropanoate but not by an alpha2 antagonist yohimbine. In cortical slices, NS-105 (10(-8)-10(-7) M) inhibited forskolin-stimulated cAMP accumulation but enhanced isoproterenol-stimulated cAMP accumulation, as did by a GABA(B) agonist (-)baclofen. On the other hand, (-)baclofen, while it significantly inhibited cAMP accumulation in slices, did no longer inhibit cAMP accumulation, when treated with NS-105 (10(-8)-10(-5) M). Similarly, (-)baclofen-induced inhibition of the cAMP accumulation was reversed by 1S,3R-ACPD and UK-14,304. NS-105 (10(-6)) increased [35S]GTPgammaS binding in the intact but not digitonin-permeabilized cortical membranes, as produced by UK-14,304, although the compound (10(-9)-10(-3) M) had no influence on various neurotransmitter receptor bindings, including alpha2 receptors. These results suggest that NS-105 modulates adenylate cyclase activity by stimulating mGluRs which might coupled to both Gi/Go and Gs.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Adrenergic alpha-Agonists; Alanine; Animals; Baclofen; Brimonidine Tartrate; Cell Membrane; Cerebral Cortex; Cholera Toxin; Cognition; Colforsin; Cyclic AMP; Cycloleucine; Excitatory Amino Acid Antagonists; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); In Vitro Techniques; Isoproterenol; Kinetics; Male; Manganese; Pertussis Toxin; Piperidines; Proline; Quinoxalines; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Receptors, Neurotransmitter; Virulence Factors, Bordetella; Yohimbine

DL-2-Amino-3-phosphonopropionic acid, a phosphonate-substituted derivative of aspartic acid, has been shown to be an inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis in rat brain slices. In this study, the enantiomers of 2-amino-3-phosphonopropionic acid were synthesized and used to further characterize the stereoselectivity and mechanism of interaction of this compound for inhibiting phosphoinositide-coupled (metabotropic) excitatory amino acid receptors. L-2-Amino-3-phosphonopropionic acid was 3-5 times more potent than D-2-amino-3-phosphonopropionic acid as an inhibitor of ibotenate-stimulated [3H]inositol monophosphate formation in slices of the rat hippocampus or quisqualate-stimulated [3H]inositol monophosphate formation in neonatal rat cerebral cortical slices. Carbachol-stimulated phosphoinositide hydrolysis was not inhibited by L-2-amino-3-phosphonopropionic acid, and L-2-amino-3-phosphonopropionic acid had no appreciable affinity for ionotropic excitatory amino acid receptors at concentrations required to inhibit metabotropic excitatory amino acid responses. The inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid on phosphoinositide hydrolysis were not competitive, because they could not be surmounted by increasing concentrations of ibotenate or quisqualate. L-2-Amino-3-phosphonopropionic acid inhibition also could not be prevented by washing the tissue before incubation with ibotenate. Thus, L-2-amino-3-phosphonopropionic acid is a stereoselective inhibitor of metabotropic excitatory amino acid receptors with little affinity for ionotropic receptors. However, the inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid were not readily reversed, and the site at which they act to inhibit metabotropic excitatory amino acid receptors remains to be determined.

Topics: Alanine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Aminobutyrates; Animals; Aspartic Acid; Brain; Hydrolysis; Ibotenic Acid; Inositol Phosphates; Kainic Acid; Male; N-Methylaspartate; Pipecolic Acids; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Stereoisomerism