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PubMed1979

Formation of N-nitrosamines from seconday animes and nitrite by resting cells of Escherichia coli B.

In the presence of resting cells of Escherichia coli B, the formation of N-nitrosamines from nitrite and secondary amines, such as dimethylamine and piperidine, was proportional to the incubation time and to the cell concentration. Optimum pH was 8.0. Boiled cells were incapable of nitrosating secondary amines. Although these experiments were carried out by using intact cells of E. coli B, the reaction followed Michaelis-Menten kinetics, and the apparent Km values calculated from Lineweaver-Burk plots were 0.12 +/- 0.03 M for dimethylamine and 0.07 +/- 0.02 M for nitrite. The apparent Km for piperidine was 0.15 +/- 0.05 M. The nitrosation was inhibited by high substrate concentrations. These results suggested that the formation of n-nitrosamines by resting cells of E. coli B apparently depends on their enzyme activities.

Dimethylamines↗

PubMed1998

Degradation of morpholine by an environmental Mycobacterium strain involves a cytochrome P-450.

A Mycobacterium strain (RP1) was isolated from a contaminated activated sludge collected in a wastewater treatment unit of a chemical plant. It was capable of utilizing morpholine and other heterocyclic compounds, such as pyrrolidine and piperidine, as the sole source of carbon, nitrogen, and energy. The use of in situ 1H nuclear magnetic resonance (1H NMR) spectroscopy allowed the determination of two intermediates in the biodegradative pathway, 2-(2-aminoethoxy)acetate and glycolate. The inhibitory effects of metyrapone on the degradative abilities of strain RP1 indicated the involvement of a cytochrome P-450 in the biodegradation of morpholine. This observation was confirmed by spectrophotometric analysis and 1H NMR. Reduced cell extracts from morpholine-grown cultures, but not succinate-grown cultures, gave rise to a carbon monoxide difference spectrum with a peak near 450 nm, which indicated the presence of a soluble cytochrome P-450. 1H NMR allowed the direct analysis of the incubation medium containing metyrapone, a specific inhibitor of cytochrome P-450. The inhibition of morpholine degradation was dependent on the morpholine/metyrapone ratio. The heme-containing monooxygenase was also detected in pyrrolidine- and piperidine-grown cultures. The abilities of different compounds to support strain growth or the induction of a soluble cytochrome P-450 were assayed. The results suggest that this enzyme catalyzes the cleavage of the C-N bond of the morpholine ring.

Acetates↗

PubMed2003

Biodegradation of cyclic amines by a Pseudomonas strain involves an amine mono-oxygenase.

Pseudomonas putida O1G3 catalyzes the degradation of pyrrolidine and piperidine. This strain can use these compounds as the sole source of carbon, nitrogen, and energy. When the cyclic amines were used as the growth substrates, the synthesis of a soluble heme amine mono-oxygenase was induced in this bacteria. This observation was confirmed by spectrophotometric analysis and specific inhibitor. This mono-oxygenase is a NADH-dependent enzyme and catalyzes the cleavage of the C-N bond of the pyrrolidine and piperidine ring by a mechanism similar to a N dealkylation. This reaction could be followed by ring cleavage to form gamma-aminobutyraldehyde oxidized to gamma-aminobutyrate. Further investigations to purify the heme-containing mono-oxygenase are in progress.

Amines↗

PubMed1985

Imino acid and related alicyclic amine levels in biological fluids.

Imino acid and related alicyclic amine concentrations in blood and urine of mammals including humans were concurrently determined by a selected ion monitoring technique. Nanomole levels of proline and pipecolic acid, and pyrrolidine and piperidine as well, were found in human urine. Proline levels but not pipecolic acid levels were higher in blood of humans than in urine. Pyrrolidine and piperidine levels in blood of humans were picomole levels and much lower than those in urine. Similar tendencies were also recognized when these 4 compounds were analyzed using animal blood and urine, although the levels were generally higher in animals than in humans. Significantly high concentrations of the imino acids and the amines were found also in animal semen.

Amines↗

PubMed2002

Photohydrolysis of methotrexate produces pteridine, which induces poly-G-specific DNA damage through photoinduced electron transfer.

Methotrexate (MTX), an antineoplastic agent, demonstrates phototoxicity. The mechanism of damage to biomacromolecules induced by photoirradiated MTX was examined using 32P-labeled DNA fragments obtained from a human gene. Photoirradiated MTX caused DNA cleavage specifically at the underlined G in 5'-GG and 5'-GGG sequences in double-stranded DNA only when the DNA fragments were treated with piperidine, which suggests that DNA cleavage was caused by base modification with little or no strand breakage. With denatured single-stranded DNA the damage occurred at most guanine residues. The amount of formation of 8-hydroxy-2'-deoxyguanosine (8-oxodGuo), an oxidative product of 2'-deoxyguanosine, in double-stranded DNA exceeded that in single-stranded DNA. These results suggest that photoirradiated MTX participates in 8-oxodGuo formation at the underlined G in 5'-GG and 5'-GGG sequences in double-stranded DNA through electron transfer, and then 8-oxodGuo undergoes further oxidation into piperidine-labile products. Fluorescence measurement, high-pressure liquid chromatography and mass spectrometry have demonstrated that photoexcited MTX is hydrolyzed into 2,4-diamino-6-(hydroxymethyl)pteridine (DHP). DNA damage induced by DHP was observed in a similar manner as was the damage induced by MTX. The extent of DNA damage and the formation of 8-oxodGuo by DHP were much larger than those induced by MTX. The kinetic analysis, based on the time course of DNA oxidation by photoirradiated MTX, suggests that DNA damage is caused by photoexcited DHP rather than by photoexcited MTX. In conclusion, photoexcited MTX undergoes hydrolysis through intramolecular electron transfer, resulting in the formation of DHP, which exhibits a phototoxic effect caused by oxidation of biomacromolecules through photoinduced electron transfer.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Unique response of double-stranded oligonucleotides containing a single 8-oxo-7,8-dihydroguanine to gamma rays in the frozen aqueous state at 77 K.

Two kinds of double-stranded oligonucleotides containing a single 8-oxo-7,8-dihydroguanine were labeled with (32)P at their 5' ends and exposed to gamma rays in the frozen aqueous state at 77 K, where both direct and quasi-direct effects of ionizing radiation predominate. Analysis of the oligonucleotides with 20% denaturing polyacrylamide gel electrophoresis revealed no difference in the immediate induction of strand breaks between oligonucleotides containing 8-oxo-7,8-dihydroguanine and their corresponding oligonucleotides with normal guanine, but piperidine-sensitive damage was induced more frequently in the former than in the latter. Sequence analysis of irradiated oligonucleotides showed that not only 8-oxo-7,8-dihydroguanine but also its neighboring bases and the cytosine residue that is paired to it became piperidine-sensitive in both oligonucleotides. These results suggest that 8-oxo-7,8-dihydroguanine, its neighboring bases and the opposite cytosine are candidates for radiation damage hot spots.

Cold Temperature↗

PubMed2006

Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity.

In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.

Animals↗

PubMed1998

Synthesis and dopaminergic features of six novel 3-arylpiperidines.

Four substituted 3-aryl-1-¿2-[5-(1H-benzimidazole)]ethyl¿piperidines and two 3-aryl-1-¿2-[6-(1,4-dihydroxyquinoxaline-2,3-dione)]ethyl¿ piperidines were synthesized, characterized and evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of fresh bovine caudate nuclei and hippocampi as a source of the dopamine and serotonin receptors, respectively, and the corresponding specific radioligands. All six novel compounds expressed no binding affinity at the D1 and 5-HT1A receptors. Derivatives of 1,4-dihydroxyquinoxaline-2,3-dione (compounds 8a and 8b) and of 2-dihalomethylbenzimidazole (ligands 9 and 10) were moderate competitors of [3H]spiperone binding at the D2 dopamine receptors. However, benzimidazole-2-thiones (compounds 7a and 7b) behaved as selective D2 receptor ligands with the binding affinity in the nanomolar range of concentrations.

Animals↗

PubMed1999

Laboratory evaluation of AI3-37220, AI3-35765, CIC-4, and deet repellents against three species of mosquitoes.

Four repellents, N,N-diethyl-3-methyl-benzamide (deet), 2-hydroxy-methyl-cyclohexyl acetic acid lactone (CIC-4), and 2 piperidines (1-[3-cyclohexen-1-ylcarbonyl] piperidine [AI3-35765] and 1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine [AI3-37220]) were evaluated alone and in combination against Aedes aegypti, Anopheles stephensi, and Culex quinquefasciatus using a modified in vitro test system. This method was a valuable tool for comparing effective concentrations of the new compounds. Because of the controlled conditions of the test, it was possible to use the results of assays that had been conducted over a 5-year period and to perform the many replications necessary to evaluate combinations of compounds. The new candidate repellents were generally as effective as deet. Although speculative at this time, there was some evidence of synergistic interaction. Repellent combinations of CIC-4/AI3-37220/AI3-35767, deet/AI3-35765, and deet/AI3-37220/AI3-35765 against An. stephensi and CIC-4/AI3-35765, deet/AI3-37220/AI3-35765, AI3-37220/AI3-35765, and CIC-4/AI3-37220 against Ae. aegypti were more effective than the component compounds alone.

Aedes↗

PubMedDate not supplied

[Polyamine oxidative deamination in hepatomas with varying growth rates].

Rates of oxidative deamination of polyamines were studied in rapidly growing hepatomas G-22 and G-27, in slowly growing hepatomas G-60, G-61, G-48, G-46 as well as in liver tissue of tumor-bearing animals and animals treated with nitrose piperidine. Diamine oxidase activity was not found in rapidly growing hepatomas. Treatment with pyridoxal-phosphate did not restore the diamine oxidase activity in hepatomas G-27, but distinctly increased the latter in the liver tissue of the tumor-bearing animals up to the level of the enzymatic activity found in liver tissue of the intact animals. On the contrary, high concentrations of pyridoxal-phosphate (above 0.02 mg) inhibited the diamine oxidase activity in liver tissue of the impaired and intact animals. The enzymatic activity was markedly decreased in slowly growing hepatomas G-60, G-61, G-48 and G-46 as compared with the activity in liver tissue of tumor-bearing animals. Oxidation of all the substrates used could be measured using hepatoma G-60, putrescine and spermidine - for hepatoma G-61, but only putrescine - for hepatoma G-48. No of the substrates used was deaminated by hepatoma G-46. Four-fold decrease in the diamine oxidase activity was observed during malignization of liver cells induced by nitrose piperidine. The diamine oxidase was mainly localized in the postmitochondrial fraction of hepatocytes.

Amine Oxidase (Copper-Containing)↗

PubMed2001

Beef cattle losses after grazing Lupinus argenteus (silvery lupine).

Ten yearling steers weighing 270-360 kg died acutely after eating early seed pod stage Lupinus argenteus (silvery lupine) containing high levels of piperidine alkaloids, including ammodendrine and N-methylammodendrine. Reduced availability of Quality feed from range moderately depleted of Quality grasses appeared a major factor in causing the cattle to graze lupine. Proximate analysis of whole plant, seed pods and seed showed high levels of crude protein ranging from 16.4 to 48% for whole plant and seed. Alkaloid analysis of the whole plant and individual plant parts such as seed and seed pods (30-40% seed shatter) showed total alkaloid levels ranging from 0.70 to 2.5% (0.70-2.5 mg/100 mg plant) dry weight. Ammodendrine levels ranged from 0.24% in seed pods with >70% seed loss to 1.35% in early growth plant with no seed. N-methylammodendrine levels ranged from 0.38% in seed pods with >70 % seed shatter to 1.04 % in pure seed. Other minor alkaloids totaled 0.08% in seed pods with >70% seed shatter to 0.60% in early growth plant before seed pod formation. These cattle ate an estimated 1.8 g/kg dry weight (486 g to 648 g) of lupine in 24 h. This appears the first report of acute death in cattle associated with piperidine alkaloid-containing Lupinus argenteus.

Alkaloids↗

PubMedDate not supplied

[Neonatal EEG trace of burst suppression. Etiological and evolutionary factors].

INTRODUCTION: The electroencephalographic (EEG) trace seen during the neonatal period which shows so called discharges of burst suppression, is caused by a severe disorder of cerebral electrogenesis occurring at this time. OBJECTIVE: To determine the aetiology, clinical significance and evolution of a group of newborn babies with this type of EEG trace. PATIENTS AND METHODS: We made a retrospective study of fullterm babies in whom burst suppression EEG recordings had been obtained during the neonatal period. RESULTS: We studied 34 patients. In 14 cases the trace was associated with hypoxic ischemic encephalopathy; 4 with meningitis; another 4 with early infantile epileptic encephalopathy (Ohtahara syndrome); 4 cases were attributed to drugs (4 with fentanyl associated in one case with phenobarbitone and in another with midazolam); 2 cases were due to early myoclonic epilepsy; 3 to multiple organ failure; one to non ketotic hyperglycinemia and another to leucinosis. In one patient the aetiology could not be determined. Seven patients died before the age of 6 months. Severe neurological sequelae were seen in all the others except for four cases (3 treated with fentanyl and one case with hypoxic ischemic encephalopathy). CONCLUSIONS: The presence of a burst suppression EEG trace in a neonate makes extensive study to determine the aetiology necessary. Although associated with a worse prognosis, those not treated with piperidine derivatives should be classified separately. Those treated with piperidine derivatives have a good prognosis.

Calcium Channel Blockers↗

PubMed1976

Mass spectrometry as an aid in the detection and identification of piperidyl benzilates and related glycolates.

On the basis of the data presented above the following conclusions may be drawn. 1. The molecular ion peaks of most of the compounds examined are relatively weak but usually easily discernible to permit molecular weight determination. 2. The mass spectra of benzilate esters exhibit a relatively intense peak at m/e 183, and monitoring of this ion can serve as a means for preliminary screening for the presence of this type of a system. 3. Related esters exhibit a similar type of fragmentation resulting in a fragment ion analogous to m/e 183 but shifted by the appropriate number of mass units according to the substituents present. 4. Cleavage of the piperidine ring-ester oxygen bond in 3 and 4-substituted isomers is followed by selective losses of hydrogen radicals to produce ions of type e, f, and g as indicated above. It is significant that in a related piperidine ring system (methylphenidate) substituted in the 2 position, the same type of cleavage results in no further hydrogen losses [16] because of charge stabilization from the ring nitrogen (ion j, Fig. 17) [17]. In other words, the tendency to form a conjugated ion following initial bond cleavage can serve as a means for identifying the position of substitution on the ring and for distinguishing positional isomers.

Benzilates↗

PubMed1992

Molecular determinants of mu receptor recognition for the fentanyl class of compounds.

We report here a theoretical study of a series of fentanyl analogs with a wide range of affinities and selectivities at the mu receptor, designed to identify and characterize the molecular determinants of mu receptor recognition. In this work, a complete conformational search combining nested rotations and molecular dynamic simulations has been made, leading to identification of accessible conformers for all analogs and to the selection of a candidate bioactive form. In addition, electronic properties have been calculated and examined as possible modulators of recognition at the mu receptor. The results of these studies have led to a distinct pharmacophore for interaction at the mu receptor for this class of compounds, with the piperidine ring in a chair conformation and the N-phenethyl and 4-phenylpropanamide substituents both equatorial. Moreover, four key moieties necessary for optimum receptor recognition and a postulated role for each of them in this recognition have been identified. These are (i) a protonated amine nitrogen, assumed to be involved in an initial electrostatic interaction with a negatively charged site on the receptor; (ii) a polar function capable of hydrogen-bonding with an electrophilic site; (iii) an aromatic ring involved in lipophilic interaction with a similar moiety; and (iv) a second aromatic ring, most probably involved in electron transfer interaction with the receptor. These requirements, taken together, form the basis of our proposed mechanism for mu receptor recognition. Not only is the presence of these components required for recognition, but specific steric relationships between them have been determined, implying the appropriate arrangement for interaction with complementary receptor sites. These steric parameters are pseudobond angles and one torsion angle that determine the relative spatial arrangement of these four moieties. They are the angles theta 1 and theta 3, defining the relative position of the protonated nitrogen and the polar function with each of the two aromatic rings, and the torsion angle eta 1, defining the orientation of the lone pair(s) on the polar proton-accepting function with respect to the lone pair on the piperidine nitrogen. This postulated mechanism of recognition provides a conceptual framework to understand why some compounds do and some do not recognize the mu receptor.

Fentanyl↗

PubMed1992

Pharmacological characterization of in vivo [3H]lfenprodil binding sites in the mouse brain.

Intravenous injection of 5 muCi of [3H]ifenprodil to mice resulted in an accumulation of radioactivity in the whole brain which was maximal at 5 min postinjection and then declined in a biphasic manner. When whole brain radioactivity was measured 2 h after [3H]ifenprodil injection, more than 65% of the incorporated label was displaced by i.p. administration (30 min before the radiotracer) of the ifenprodil chemical congener +/-alpha-(4-chlorophenyl)-4-(4- fluorophenylmethyl)-1-piperidine ethanol (SL 82.0715) (10 mg/kg). At this time, most of the radioactivity (80%) present in the brain comigrated with authentic [3H]ifenprodil. When administered 30 min before the radiotracer, several sigma ligands inhibited in vivo [3H]ifenprodil binding to the mouse brain with the following rank order of potency (ID50, mg/kg, i.p.): haloperidol (0.27) greater than ifenprodil (0.83) greater than SL 82.0715 (1.37) greater than BMY 14,802 (5.5) greater than 1,3-di-O-tolylguanidine (18). GBR 12909 (20 mg/kg, i.p.) and phencyclidine (30 mg/kg, i.p.) also inhibited this binding by 71 and 59%, respectively. In contrast, the N-methyl-D-aspartate receptor channel blockers 1-[1-(2-thienyl)cyclohexyl] piperidine and MK-801 (10 mg/kg, i.p.) failed to affect [3H]ifenprodil binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Synthesis and antinociceptive activity of 2- and 3-methyl derivatives of 4-(pyridyl) isosteres of meperidine.

The respective cis- and trans-[3-Me,4-(pyridyl)] diastereoisomers of 4-(2-pyridyl)- (8a and 8b), 4-(3-pyridyl)- (8d and 8e) and 4-(4-pyridyl)-1,3-dimethyl-4-ethoxycarbonylpiperidines (8h and 8i) were synthesized for evaluation as 3-methyl substituted isosteres of meperidine. Alkylation of ethyl 2-, 3- or 4-pyridylacetate (7) with N-(2-chloroethyl)-N-(2-chloropropyl)methylamine (6) afforded the respective 3-methyl substituted compounds 8a and 8b, 8d and 8e or 8h and 8i, together with the corresponding 2-methyl substituted compounds 8c (only the trans-isomer was obtained), 8f and 8g, or 8j and 8k. Antinociceptive test results, acquired using the 4% sodium chloride assay in rats, indicated that a cis-3-methyl substituent usually enhanced antinociceptive potency slightly, whereas a trans-3-methyl substituent lowered activity 3-4 fold relative to the parent 3-unsubstituted compounds 3b-d, at a dose of 2 mg/kg sc. A trans-2-methyl substituent (8g and 8k), like a cis-methyl substituent (8a, 8d and 8h), also maintained or provided a small increase in antinociceptive activity. Trans-1,2-Dimethyl-4-ethoxycarbonyl-4-(3-pyridyl)piperidine (8g) and cis-1,3-dimethyl-4-ethoxycarbonyl-4-(4-pyridyl)piperidine (8h) were the most active antinociceptives producing a 66% inhibition of writhing at a dose of 2 mg/kg sc, relative to the reference drug meperidine (ED50 = 0.6 mg/kg sc).

Analgesics↗

PubMed1991

Electrophysiological and binding studies on intact NCB-20 cells suggest presence of a low affinity sigma receptor.

Whole cell voltage clamp studies were performed on NCB-20 cells to examine physiological responses to drugs possessing affinities for sigma receptors. Those drugs [haloperidol, alpha-(4-fluoro-phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutano l (BMY-14802), pentazocine, N-allylnormetazocine (SKF-10047), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP), phencyclidine, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine maleate (MK-801)] caused an apparent inward current, which was due to blockade of a tonic, outward potassium current. The rank order of drug potencies in producing this effect generally resembled the rank orders of sigma-receptor affinities for the drugs, except that a reverse stereoselectivity was observed for several drugs. [3H](+)-SKF-10047 labeled two sites in intact NCB-20 cells (Kd = 49 nM, Bmax = 1.0 pmol/mg protein and Kd = 9.6 microM, Bmax = 69 pmol/mg protein). The high affinity site was similar pharmacologically to the sigma receptor assayed in membrane fragments from NCB-20 cells. However, the low affinity site showed a slightly different profile, highlighted by a reverse stereoselectivity. The rank order of drug potencies was as follows at the low affinity site: haloperidol greater than BMY-14802 greater than (-)-pentazocine greater than (+)-pentazocine greater than (-)-SKF-10047 greater than (-)-3-PPP greater than (+)-SKF-10047 greater than (+)-3-PPP greater than phencyclidine greater than TCP greater than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Ifenprodil and SL 82.0715 as cerebral antiischemic agents. III. Evidence for antagonistic effects at the polyamine modulatory site within the N-methyl-D-aspartate receptor complex.

Ifenprodil and SL 82.0715 are noncompetitive N-methyl-D-aspartate (NMDA) antagonists whose inhibitory actions are not explained by antagonistic effects at any of the three commonly recognized sites within the NMDA receptor complex (recognition, channel and modulatory glycine sites). We presently show that ifenprodil and SL 82.0715 antagonize the effects of NMDA via a selective action at the recently described polyamine modulatory site. Spermine and spermidine (0.5-100 microM) increase the binding of [3H]1-[1-(2-thienyl)cyclohexyl] piperidine to washed rat forebrain membranes in the presence of glutamate (10 microM). This effect is antagonized by ifenprodil and SL 82.0715 (0.1-10 microM) at concentrations which do not displace [3H]1-(2-thienyl)cyclohexyl] piperidine in the absence of added polyamine. Spermine and spermidine (up to 100 microM) do not significantly alter the binding of [3H]glycine but increase the binding of the NMDA recognition site ligand [3H](+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. Ifenprodil and SL 82.0715 (0.1-10 microM) antagonize this effect; ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate) or 7-chlorokynurenate (100 microM) are ineffective. In immature rat cerebellar slices, spermine and spermidine (10-1000 microM) potentiate the maximal effects of NMDA (80-160 microM) on cyclic GMP production. Spermine (100-1000 microM) reverses the antagonistic effects of ifenprodil (0.15-50 microM) but not of ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine acid or kynurenate on the NMDA receptor-mediated increase in cyclic GMP levels. Ifenprodil (0.01-1 microM) potently but only partially antagonizes the depolarizing effects of NMDA (10 microM) on the immature rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗