cyclic-gmp and ifenprodil

1. Antagonists acting at the polyamine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including a number of heterocyclic aminoalcohols related to ifenprodil, were investigated to establish their functional interaction at the NMDA receptor and their neuroprotective profile. 2. In murine cultured neocortical neurones, NMDA (100 microM)-stimulated production of guanosine 3':5'-cyclic monophosphate (cyclic GMP) was blocked by N-1([thienyl]-cyclohexyl)-piperidine (1 microM) and by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (100 microM). Ifenprodil and structurally related heterocyclic aminoalcohols inhibited in a concentration-dependent manner the NMDA-stimulated, NO-dependent production of cyclic GMP; rank potency order was: ifenprodil > 2309 BT > tibalosine > threo-tibalosine > 840S. 3. All of the polyamine NMDA antagonists blocked NMDA (300 microM)-stimulated increases in intracellular calcium concentrations as measured by changes in the fluorescence of pre-loaded fluo-3-acetoxy methyl ester. Rank potency order was: ifenprodil > 2309 BT > 840S > tibalosine > threo-tibalosine. 4. In a series of experiments to evaluate the effectiveness of the polyamine NMDA antagonists as blockers of NMDA-induced cytotoxicity, all of the drugs were found to inhibit the leakage of lactate dehydrogenase after the exposure of the murine neocortical cultures to NMDA (100 microM, 5 h). Rank potency order was: 2309 BT > ifenprodil > tibalosine > threo-tibalosine > 840S. 5. These results provide direct evidence that polyamine NMDA antagonists produce a functional blockade of the NMDA receptor complex. The heterocyclic amino alcohols described herein, likeifenprodil, block NMDA-mediated elevation of intracellular NO and calcium, two key events in the excitotoxic cascade, and are cytoprotective.

Topics: Animals; Calcium; Cells, Cultured; Cyclic GMP; Dose-Response Relationship, Drug; Female; Mice; N-Methylaspartate; Neurons; Piperidines; Propanolamines; Receptors, N-Methyl-D-Aspartate

In the present investigation, the effects of polyamines, spermidine and spermine on events mediated by the N-methyl-D-aspartate (NMDA) receptor complex were examined. Spermine and spermidine did not alter basal levels of cyclic GMP (cGMP) in the cerebellum of the mouse, over a wide range of concentrations. However, exogenously added spermine, spermidine, D- and L-ornithine and putrescine attenuated the increases in cGMP seen after the administration of D-serine, an agonist of the NMDA receptor-associated glycine recognition sites. Spermine and/or spermidine also antagonized harmaline-, methamphetamine- and pentylenetetrazol-induced increases in the levels of cGMP. Spermidine also potentiated (+)-MK-801 (dizocilipine)-induced attenuation of basal levels of cGMP. Intracerebroventricular administration of ifenprodil, a suggested polyamine antagonist, did not antagonize spermine- and spermidine-induced attenuation of the response to D-serine. These data suggest that exogenously added polyamines attenuate events mediated by the NMDA receptor complex, in an ifenprodil-insensitive manner.

Topics: Animals; Biogenic Polyamines; Cerebellum; Cyclic GMP; Dizocilpine Maleate; Injections, Intraventricular; Male; Methamphetamine; Mice; Neural Pathways; Ornithine; Pentylenetetrazole; Piperidines; Putrescine; Receptors, N-Methyl-D-Aspartate; Spermidine; Spermine

Cerebellar cyclic guanosine monophosphate (cGMP) levels reflect the ongoing neuronal activity mediated by the N-methyl-D-aspartate (NMDA) receptor complex. Due to the putative role of the NMDA receptor complex in the etiology of ischemic neuronal injury, the effects of two novel anti-ischemic agents, ifenprodil and BMY-14802, were examined on cGMP responses mediated by harmaline, methamphetamine (MA), and pentylenetetrazol (PTZ), agents which modulate the Purkinje cell activity by three distinct pharmacological mechanisms. Similar to the competitive NMDA antagonist, CPP [(+/-)-3-carboxypiperazin-4-yl)propyl-1-phosphonic acid], ifenprodil and BMY-14802 reversed the harmaline-, MA- and PTZ-induced cGMP levels. Unlike CPP, ifenprodil was nearly 3-times less potent at reversing the harmaline-induced increases in cGMP levels than at reversing MA-and PTZ-induced increases in cGMP levels. These results suggest a differential modulation of basket and stellate, and mossy fiber activity by ifenprodil.

Topics: Analysis of Variance; Animals; Cyclic GMP; Harmaline; Male; Methamphetamine; Mice; Mice, Inbred Strains; Neurons; Pentylenetetrazole; Piperazines; Piperidines; Purkinje Cells; Pyrimidines; Radioimmunoassay; Receptors, Amino Acid; Receptors, Cell Surface

Topics: Adrenergic alpha-Antagonists; Animals; Cerebellum; Cyclic GMP; Glycine; Injections; Male; Mice; Piperidines; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Serine; Time Factors

The effects of the anti-ischemic agents ifenprodil and its derivative SL 82.0715 ((+/-)-alpha-(4-chlorophenyl)-4-[(4-fluorophenyl) methyl]-1-piperidineethanol] have been analyzed in a number of models indicative of N-methyl-D-aspartate (NMDA) antagonistic potential in vitro and in vivo. Ifenprodil and SL 82.0715 potently and noncompetitively antagonize the stimulatory effects of NMDA on cyclic GMP production in immature rat cerebellar slices (IC50 values, 0.4 and 10 microM, respectively), as well as the NMDA-evoked [3H]acetylcholine release in adult rat striatal slices (IC50 values, 1.6 and 6.6 microM, respectively). Ifenprodil is 10 times more potent than (+/-)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) but less active than the reference noncompetitive NMDA channel blockers [MK 801, ((+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine ], phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP)] in these models. Ifenprodil and SL 82.0715 partially displace (maximal displacement 40-50% at 10 microM) the NMDA receptor ligand [3H]CPP from its binding site to rat brain membranes (IC50 values, 0.1 and 0.3 microM, respectively) in a noncompetitive manner; in the micromolar range the two agents also partially displace the NMDA channel ligand [3H]TCP from its binding site to rat brain membranes, and noncompetitively antagonize the L-glutamate-induced increase in [3H]TCP binding. Ifenprodil (0.01-1 microM) partially antagonizes the depolarizing effects of NMDA on the immature rat hemisected spinal cord in vitro. In mouse cultured spinal cord neurons, ifenprodil dose-dependently antagonizes the depolarizing effects of micropressure applied NMDA. Inhibition of the effects of NMDA in this model by ifenprodil and SL 82.0715 is noncompetitive. In vivo and after systemic i.p. administration, ifenprodil and SL 82.0715 antagonize the stimulatory effects of intrastriatally dialyzed NMDA on striatal dopamine release in rats (ID50 values, 0.9 and 0.3 mg/kg, respectively), and block the harmaline-evoked increase in cerebellar cyclic GMP production in mice (ID50 values, 3 and 4 mg/kg, respectively). These results indicate that ifenprodil is a noncompetitive NMDA antagonist which has a mechanism of action distinct from either the reference competitive NMDA receptor antagonists (CPP and 2-amino-5-phosphonovalerate) or the noncompetitive NMDA channel blockers (phencyclidine, TCP and MK 801). The potent NMDA antagonistic effects of the ifenprodil c

Topics: Animals; Aspartic Acid; Brain Ischemia; Cells, Cultured; Cerebellum; Corpus Striatum; Cyclic GMP; Dopamine; Harmaline; In Vitro Techniques; Mice; N-Methylaspartate; Phencyclidine; Piperazines; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord