73 results on '"Koe BK"'
Search Results
2. ISOLATION AND CHARACTERIZATION OF URINARY METABOLITES OF BENZQUINAMIDE AND BENZQUINAMIDE ALCOHOL
- Author
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Pinson R and Koe Bk
- Subjects
Chromatography ,Isolation (health care) ,Ethanol ,Chemistry ,Urinary system ,medicine.condition_prevention_factors ,Research ,Alcohol ,Urine ,Glucuronidase ,chemistry.chemical_compound ,Dogs ,Metabolism ,Tranquilizing Agents ,Benzquinamide ,Drug Discovery ,medicine ,Molecular Medicine ,Animals ,Quinolizines - Published
- 1964
3. Sertraline potently displaces (+)-[3H]3-PPP binding to σ sites in rat brain
- Author
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Koe Bk, James Heym, Lorraine A. Lebel, Anne W. Schmidt, and Seeger T
- Subjects
Brain Chemistry ,Pharmacology ,medicine.medical_specialty ,Sertraline ,Chemistry ,In Vitro Techniques ,Naphthalenes ,Rat brain ,Binding, Competitive ,Molecular biology ,Rats ,1-Naphthylamine ,Endocrinology ,Piperidines ,Receptors, Opioid, delta ,Internal medicine ,Receptors, Opioid ,medicine ,Animals ,Serotonin Antagonists ,medicine.drug - Abstract
Des experiences realisees sur des cerveaux de rat ont montre que la sertraline, antidepresseur antiserotoninergique, presentait une affinite importante pour les recepteurs σ situes dans le systeme limbique et le cortex et impliques dans les troubles psychotiques, puisqu'elle etait capable de deplacer le (+)-[ 3 H] 3 PPP de ses sites recepteurs σ. Bien que l'affinite de la sertraline soit moins importante que celle de l'haloperidol (antipsychotique moyen) elle est plus importante que l'affinite d'autres substances tels le rimicazole, le BMY-14802 ou la pentazocine
- Published
- 1989
- Full Text
- View/download PDF
4. 6-Aminopenicillanamide and Methyl 6-Aminopenicillanate
- Author
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Koe Bk
- Subjects
Acylation ,Penicillin ,Multidisciplinary ,Simple (abstract algebra) ,Chemistry ,education ,mental disorders ,polycyclic compounds ,medicine ,Penicillins ,Combinatorial chemistry ,psychological phenomena and processes ,medicine.drug - Abstract
SIMPLE derivatives of penicillins, such as esters1 and amides2, have been prepared from the penicillins themselves by conventional methods. The availability of 6-aminopenicillanic acid (6-APA) led me to synthesize from it selected carboxylic derivatives which can be used conveniently to prepare corresponding series of penicillin derivatives by acylation of the appropriate 6-APA intermediate.
- Published
- 1962
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5. Effects of serotoninergic agents on downregulation of beta-adrenoceptors by the selective serotonin reuptake inhibitor sertraline.
- Author
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Koe BK and Lebel LA
- Subjects
- 1-Naphthylamine pharmacology, 8-Hydroxy-2-(di-n-propylamino)tetralin administration & dosage, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, Binding, Competitive, Dihydroalprenolol metabolism, Drug Interactions, Drug Synergism, Male, Methiothepin administration & dosage, Methiothepin pharmacology, Norfenfluramine administration & dosage, Norfenfluramine pharmacology, Ondansetron pharmacology, Piperazines pharmacology, Pyrimidines administration & dosage, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta metabolism, Ritanserin pharmacology, Serotonin Antagonists administration & dosage, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists administration & dosage, Serotonin Receptor Agonists pharmacology, Sertraline, 1-Naphthylamine analogs & derivatives, Down-Regulation drug effects, Receptors, Adrenergic, beta drug effects, Serotonin Agents pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
The results of the present study show that the down-regulation of beta-adrenoceptors of rat brain, induced by subacute administration of sertraline, is facilitated when this selective serotonin reuptake inhibitor was co-administered with the serotonin releaser, norfenfluramine, or the serotonin terminal autoreceptor antagonist, methiothepin. The respective drug combination produced a reduction in Bmax of [3H]dihydroalprenolol binding to cortical membranes of treated rats at a dose of the releaser, release enhancer, or sertraline, which was ineffective when administered alone. In a similar manner, the 5-HT1A agonists, gepirone and 8-OH-DPAT, were found to facilitate the downregulation of beta-adrenoceptors induced by sertraline. The 5-HT1B agonist, 3-trifluoromethylphenylpiperazine, and the 5-HT2 antagonist, ritanserin, showed neither facilitation nor antagonism of sertraline, but the 5-HT3 antagonist, ondansetron, attenuated the decrease of Bmax of [3H]dihydroalprenolol binding elicited by sertraline. Agents that putatively increase the serotoninergic activity facilitated the down-regulation of beta-adrenoceptors induced by sertraline, suggesting that the enhancement of serotonin transmission, expected of the selective serotonin reuptake inhibitor itself, may play a role in this effect of sertraline. Whether the downregulation of brain beta-adrenoceptors by sertraline plays any role in its antidepressant activity cannot be deduced from these experiments.
- Published
- 1995
6. 5-[(3-nitropyrid-2-yl)amino]indoles: novel serotonin agonists with selectivity for the 5-HT1D receptor. Variation of the C3 substituent on the indole template leads to increased 5-HT1D receptor selectivity.
- Author
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Macor JE, Blank DH, Fox CB, Lebel LA, Newman ME, Post RJ, Ryan K, Schmidt AW, Schulz DW, and Koe BK
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- Indoles metabolism, Indoles pharmacology, Molecular Conformation, Molecular Structure, Serotonin Receptor Agonists pharmacology, Stereoisomerism, Structure-Activity Relationship, Sumatriptan metabolism, Sumatriptan pharmacology, Indoles chemical synthesis, Receptors, Serotonin drug effects, Serotonin Receptor Agonists chemical synthesis
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- 1994
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7. Synthesis and serotonergic pharmacology of the enantiomers of 3-[(N-methylpyrrolidin-2-yl)methyl]-5-methoxy-1H-indole: discovery of stereogenic differentiation in the aminoethyl side chain of the neurotransmitter serotonin.
- Author
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Macor JE, Blake J, Fox CB, Johnson C, Koe BK, Lebel LA, Morrone JM, Ryan K, Schmidt AW, and Schulz DW
- Subjects
- Indoles pharmacology, Pyrrolidines pharmacology, Receptors, Serotonin drug effects, Receptors, Serotonin metabolism, Serotonin metabolism, Serotonin Receptor Agonists pharmacology, Stereoisomerism, Indoles chemical synthesis, Pyrrolidines chemical synthesis, Serotonin Receptor Agonists chemical synthesis
- Published
- 1992
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8. 1-(2-Aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-e]indole: a rotationally restricted phenolic analog of the neurotransmitter serotonin and agonist selective for serotonin (5-HT2-type) receptors.
- Author
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Macor JE, Fox CB, Johnson C, Koe BK, Lebel LA, and Zorn SH
- Subjects
- Animals, Indoles pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Pyrroles chemical synthesis, Pyrroles pharmacology, Rats, Receptors, Serotonin drug effects, Receptors, Serotonin metabolism, Serotonin Receptor Agonists pharmacology, Structure-Activity Relationship, Indoles chemical synthesis, Serotonin analogs & derivatives, Serotonin Receptor Agonists chemical synthesis
- Abstract
A series of rotationally restricted phenolic analogs of the neurotransmitter serotonin has been synthesized with the 5-hydroxyindole portion of serotonin replaced by a dihydropyrano[3,2-e]-indole (1, 3, 4, and 5) and a dihydropyrano[2,3-f]indole (2). The receptor binding profile of these compounds has been studied and compared to the natural substrate serotonin. The dihydropyrano[3,2-e]indole derivatives (1, 3, 4, and 5) possess lower affinity for 5-HT1 receptors but equal or greater affinity for 5-HT2 receptors. Like serotonin, these compounds dose-dependently stimulated phosphatidylinositol turnover in rat brain slices. Moreover, the response to 1-(2-aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-]indole (5, CP-132,484) and 1-(2-aminoethyl)-8,9-dihydropyrano[3,2-e]indole (4) is selectively antagonized by 5-HT2 receptor antagonists establishing these tryptamines as selective 5-HT2 receptor agonists. The high affinity and potency of 5 for 5-HT2 receptors suggests that the C5-hydroxy group in serotonin can function as a hydrogen bond acceptor in a 5-HT2 receptor with a directionality of interaction which is down and away from C6 in serotonin (Figure 5). Furthermore, the potent affinity of these compounds for 5-HT2 receptors coupled with their poor affinity for 5-HT1 receptors indicates that the aminoethyl side chain of serotonin adopts significantly different conformations in 5-HT1 versus 5-HT2 receptors.
- Published
- 1992
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9. Characterization of [3H]CP-96,501 as a selective radioligand for the serotonin 5-HT1B receptor: binding studies in rat brain membranes.
- Author
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Koe BK, Lebel LA, Fox CB, and Macor JE
- Subjects
- Animals, Binding, Competitive, Guanine Nucleotides pharmacology, Indoles antagonists & inhibitors, Indoles chemistry, Ligands, Rats, Tritium, Brain metabolism, Indoles metabolism, Receptors, Serotonin metabolism
- Abstract
3-(1,2,5,6-Tetrahydro-4-pyridyl)-5-n-propoxyindole (CP-96,501) was found to be more selective ligand at the serotonin 5-HT1B receptor than the commonly used 5-HT1B agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-methoxyindole (RU 24969). In rat brain membranes, the tritiated derivative, [3H]CP-96,501, was found to bind with a high affinity (KD, 0.21 nM) to a single binding site (nH, 1.0). The receptor density of this site (Bmax, 72 fmol/mg of protein) matched that of the 5-HT1B receptor determined with [3H]5-HT. Competition curves of 16 serotonergic compounds in [3H]CP-96,501 binding also indicated a single binding site. The rank order of their binding affinities with this new radioligand showed a high degree of correlation with their affinities at the 5-HT1B receptor determined with [3H]5-HT or [125I]iodocyanopindolol. Serotonergic compounds displayed competitive inhibition of [3H]CP-96,501 binding. In the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p], [3H]CP-96,501 to displace [125I]iodocyanopindolol binding was also decreased. These findings are consistent with the agonist nature of CP-96,501. The results of this study suggest that [3H]CP-96,501 is a useful agonist radioligand for the 5-HT1B receptor.
- Published
- 1992
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10. Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
- Author
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Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, and Fox CB
- Subjects
- Adrenergic alpha-Antagonists chemistry, Animals, Molecular Structure, Piperidines metabolism, Piperidines pharmacology, Rats, Receptors, Adrenergic, alpha drug effects, Receptors, Adrenergic, alpha metabolism, Receptors, N-Methyl-D-Aspartate drug effects, Receptors, N-Methyl-D-Aspartate metabolism, Stereoisomerism, Structure-Activity Relationship, Adrenergic alpha-Antagonists pharmacology, N-Methylaspartate antagonists & inhibitors, Piperidines chemistry
- Abstract
Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
- Published
- 1991
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11. Structure-activity relationship of quinazolinedione inhibitors of calcium-independent phosphodiesterase.
- Author
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Lowe JA 3rd, Archer RL, Chapin DS, Chen JB, Helweg D, Johnson JL, Koe BK, Lebel LA, Moore PF, and Nielsen JA
- Subjects
- Animals, Brain drug effects, Brain metabolism, Chemical Phenomena, Chemistry, Male, Mice, Phosphodiesterase Inhibitors metabolism, Phosphodiesterase Inhibitors pharmacology, Pyrrolidinones metabolism, Pyrrolidinones pharmacology, Quinazolines metabolism, Quinazolines pharmacology, Rats, Rolipram, Structure-Activity Relationship, Phosphodiesterase Inhibitors chemical synthesis, Quinazolines chemical synthesis
- Abstract
A series of quinazolinediones and azaquinazolinediones is described which possess potent inhibitory activity toward the calcium-independent phosphodiesterase enzyme (CaIPDE). In vivo testing showed that this in vitro activity translates to animal models predictive of chronic diseases such as depression and inflammation. These results support the hypothesis that inhibition of CaIPDE may lead to useful activity in such chronic diseases.
- Published
- 1991
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12. Calcium-independent phosphodiesterase inhibitors as putative antidepressants: [3-(bicycloalkyloxy)-4-methoxyphenyl]-2-imidazolidinones.
- Author
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Saccomano NA, Vinick FJ, Koe BK, Nielsen JA, Whalen WM, Meltz M, Phillips D, Thadieo PF, Jung S, and Chapin DS
- Subjects
- Animals, Body Temperature drug effects, Calcium pharmacology, Female, Indicators and Reagents, Magnetic Resonance Spectroscopy, Mice, Molecular Conformation, Molecular Structure, Motor Activity drug effects, Phosphodiesterase Inhibitors chemistry, Phosphodiesterase Inhibitors pharmacology, Pyrrolidinones pharmacology, Rats, Rats, Inbred Strains, Reserpine pharmacology, Rolipram, Structure-Activity Relationship, Antidepressive Agents chemical synthesis, Brain metabolism, Cerebral Cortex enzymology, Phosphodiesterase Inhibitors chemical synthesis
- Abstract
The synthesis and biological properties of a novel series of selective calcium-independent phosphodiesterase inhibitors are described. These compounds also inhibit the specific binding of [3H]rolipram to rat brain membranes and exhibit efficacy in preclinical models of antidepressant activity in mice, such as reducing immobility in the forced-swim test and reversing reserpine-induced hypothermia. Imidazolidinones 4 and 16 were found to be the most potent compounds studied.
- Published
- 1991
- Full Text
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13. Nicotinamide ethers: novel inhibitors of calcium-independent phosphodiesterase and [3H]rolipram binding.
- Author
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Vinick FJ, Saccomano NA, Koe BK, Nielsen JA, Williams IH, Thadeio PF, Jung S, Meltz M, Johnson J Jr, and Lebel LA
- Subjects
- Animals, Binding Sites, Body Temperature Regulation drug effects, Ethers, Indicators and Reagents, Magnetic Resonance Spectroscopy, Mass Spectrometry, Mice, Molecular Structure, Niacinamide pharmacology, Protein Binding, Pyrrolidinones pharmacology, Rats, Reserpine pharmacology, Rolipram, Structure-Activity Relationship, Brain metabolism, Niacinamide analogs & derivatives, Niacinamide chemical synthesis, Phosphodiesterase Inhibitors chemical synthesis, Pyrrolidinones metabolism
- Abstract
The synthesis and biological properties of a series of nicotinamide ethers are described. These compounds, structurally novel calcium-independent phosphodiesterase inhibitors, also inhibit the binding of [3H]rolipram to rat brain membranes and reverse reserpine-induced hypothermia in the mouse. Several compounds exhibited potent in vivo activity comparable to the standard agent, rolipram.
- Published
- 1991
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14. Preclinical pharmacology of sertraline: a potent and specific inhibitor of serotonin reuptake.
- Author
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Koe BK
- Subjects
- 1-Naphthylamine pharmacology, Animals, Down-Regulation drug effects, Drug Evaluation, Preclinical, Humans, In Vitro Techniques, Raphe Nuclei drug effects, Raphe Nuclei physiology, Rats, Receptors, Serotonin drug effects, Receptors, Serotonin physiology, Serotonin metabolism, Serotonin physiology, Sertraline, Synaptic Transmission drug effects, Synaptosomes drug effects, Synaptosomes metabolism, 1-Naphthylamine analogs & derivatives, Serotonin Antagonists pharmacology
- Abstract
Specific serotonin reuptake inhibitors constitute a new class of psychotherapeutic agents that promote enhanced central serotonergic neurotransmission in animal studies. Sertraline, a member of this class, exhibits considerable potency and specificity in inhibiting serotonin neuronal reuptake in preclinical studies. Thus, it is likely to exert antidepressant activity without significant anticholinergic, cardiovascular, and sedative side effects. Other animal studies demonstrating decreases in food intake and body weight and reduction in voluntary alcohol consumption after sertraline administration suggest a potential for wider clinical application.
- Published
- 1990
15. 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants.
- Author
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Sarges R, Howard HR, Browne RG, Lebel LA, Seymour PA, and Koe BK
- Subjects
- Adenosine analogs & derivatives, Adenosine metabolism, Adenosine pharmacology, Adenosine-5'-(N-ethylcarboxamide), Animals, Antidepressive Agents chemical synthesis, Behavior, Animal drug effects, Caffeine pharmacology, Cats, Cell Membrane metabolism, Cerebral Cortex metabolism, Chemical Phenomena, Chemistry, Corpus Striatum metabolism, Male, Molecular Structure, Motor Activity drug effects, Quinoxalines chemical synthesis, Quinoxalines metabolism, Rats, Receptors, Purinergic metabolism, Sleep drug effects, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles metabolism, Antidepressive Agents therapeutic use, Purinergic Antagonists, Quinoxalines pharmacology, Triazoles pharmacology
- Abstract
A series of 4-amino[1,2,4]triazolo[4,3-a]quinoxalines has been prepared. Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents. Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring. Furthermore, many of these 4-amino[1,2,4]triazolo[4,3-a]quinoxalines bind avidly, and in some cases very selectively, to adenosine A1 and A2 receptors. A1 affinity of these compounds was measured by their inhibition of tritiated CHA (N6-cyclohexyladenosine) binding in rat cerebral cortex membranes and A2 affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N6-cyclopentyladenosine. Structure-activity relationship (SAR) studies show that best A1 affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-iPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent. Affinity at the A2 receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position. The most selective A1 ligand by a factor of greater than 3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexyl-amino)-1- (trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 28 nM at the A1 receptor. The most potent A2 ligand is 128 (CP-66,713; 4-amino-8-chloro-1- phenyl[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 21 nM at the A2 receptor and a 13-fold selectivity for this receptor. Representatives from this series appear to act as antagonists at both A1 and A2 receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices. Thus certain members of this 4-amino[1,2,4]triazolo[4,3-a]quinoxaline series are among the most potent and A1 or A2 selective non-xanthine adenosine antagonists known.
- Published
- 1990
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16. [3H] sertraline binding to rat brain membranes.
- Author
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Koe BK, Lebel LA, and Welch WM
- Subjects
- 1-Naphthylamine analogs & derivatives, 1-Naphthylamine pharmacokinetics, Animals, Fenclonine pharmacology, Fluoxetine pharmacology, Imipramine pharmacology, In Vitro Techniques, Male, Membranes metabolism, Paroxetine, Piperidines pharmacology, Rats, Receptors, Serotonin metabolism, Serotonin Antagonists pharmacokinetics, Sertraline, 1-Naphthylamine metabolism, Brain metabolism, Naphthalenes metabolism, Serotonin Antagonists metabolism
- Abstract
Tritiated sertraline, a radiolabeled form of a potent and selective inhibitor of serotonin uptake, was found to bind with high affinity to rat whole brain membranes. Characterization studies showed that [3H] sertraline binding occurred at a single site with the following parameters: KD 0.57 nM, Bmax 821 fmol/mg protein, nH 1.06. This binding was reversible; the dissociation constant calculated from kinetic measurements (KD 0.81 nM) agreed with that determined by saturation binding experiments. [3H] Sertraline binding in the presence of serotonin, paroxetine, fluoxetine or imipramine suggested competitive inhibition of binding (large increase in KD with little change in Bmax). The rank order of potency of inhibition of [3H] sertraline binding was similar to that of inhibition of serotonin uptake for known uptake inhibitors and the 1-amino-4-phenyltetralin uptake blockers. A marked decrease in ex vivo [3H] sertraline binding in the brain of rats 7 days after treatment with p-chloroamphetamine was consistent with the loss of serotonin uptake sites induced by this agent. The results of our study indicated that [3H] sertraline labels serotonin uptake sites in rat brain.
- Published
- 1990
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17. Levonantradol, a potent cannabinoid-related analgesic, antagonizes haloperidol-induced activation of striatal dopamine synthesis.
- Author
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Koe BK
- Subjects
- Animals, Corpus Striatum metabolism, Dronabinol pharmacology, Male, Rats, Receptors, Dopamine drug effects, Stereoisomerism, gamma-Aminobutyric Acid pharmacology, Analgesics pharmacology, Dopamine biosynthesis, Haloperidol antagonists & inhibitors, Phenanthridines pharmacology
- Abstract
Levonantradol antagonized the compensatory acceleration of striatal dopamine synthesis induced by haloperidol. This effect was stereospecific, since the pharmacologically less active enantiomer, dextronantradol was approximately 30 times less effective. delta 9-Tetrahydrocannabinol at a dose 320 times higher than levonantradol also attenuated the haloperidol effect, but cannabidiol was inactive at a dose 750 times higher. GABA-like actions of levonantradol may be responsible for this responsible for this antagonism of haloperidol, but anticholinergic effects may also contribute.
- Published
- 1981
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18. Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin.
- Author
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Koe BK, Weissman A, Welch WM, and Browne RG
- Subjects
- 1-Naphthylamine analogs & derivatives, 1-Naphthylamine pharmacology, 5-Hydroxytryptophan administration & dosage, Animals, Behavior, Animal drug effects, Blood Pressure drug effects, Dogs, Dopamine metabolism, Drug Interactions, Female, Hypothermia drug therapy, Lethal Dose 50, Male, Mice, Mice, Inbred Strains, Monoamine Oxidase Inhibitors administration & dosage, Monoamine Oxidase Inhibitors pharmacology, Myocardium metabolism, Norepinephrine administration & dosage, Norepinephrine metabolism, Parasympatholytics administration & dosage, Rats, Rats, Inbred Strains, Receptors, Adrenergic drug effects, Serotonin blood, Serotonin Antagonists pharmacology, Sertraline, p-Chloroamphetamine administration & dosage, 1-Naphthylamine administration & dosage, Brain Chemistry drug effects, Naphthalenes administration & dosage, Serotonin metabolism, Serotonin Antagonists administration & dosage
- Abstract
Sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine] was found to be a highly selective and potent competitive inhibitor of synaptosomal serotonin uptake. Sertraline also selectively reduced ex vivo uptake of serotonin and strongly antagonized the serotonin-depleting action of p-chloroamphetamine, indicating potent blockade of serotonin uptake in vivo. Acute and repeated dosing of sertraline decreased serotonin content of whole blood. Sertraline only weakly inhibited rat heart uptake of i.v. [3H]norepinephrine. In substantiation of selective blockade of serotonin uptake, sertraline potentiated various symptoms of 5-hydroxytryptophan but did not reverse reserpine-induced hypothermia. Sertraline was a very weak inhibitor of [3H]quinuclidinyl benzilate binding to rat brain membranes in vitro and did not produce anticholinergic effects in mice in vivo. Sertraline was well tolerated in mice, rats and dogs, with no locomotor stimulant effects in rats or untoward cardiovascular effects in dogs. The major metabolite, N-demethylsertraline, was also a selective serotonin uptake blocker. Sertraline strongly reduced immobility of mice in the Porsolt swim test for antidepressants. After repeated dosing in rats, sertraline diminished the cyclic AMP response of limbic forebrain adenylate cyclase to norepinephrine, as well as the binding of [3H]dihydroalprenolol to cortical membranes. It is proposed that selective blockade of serotonin reuptake can induce activation of norepinephrine neurons and subsequent down-regulation of norepinephrine receptors and that sertraline, a highly selective inhibitor of serotonin uptake, may be an efficacious antidepressant without anticholinergic or cardiovascular side-effects.
- Published
- 1983
19. Synthesis and dopamine autoreceptor activity of a 5-(methylmercapto)methyl-substituted derivative of (+/-)-3-PPP (3-(3-hydroxyphenyl)-1-n-propylpiperidine).
- Author
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Kelly TR, Howard HR, Koe BK, and Sarges R
- Subjects
- 4-Butyrolactone pharmacology, Animals, Chemical Phenomena, Chemistry, Corpus Striatum drug effects, Corpus Striatum metabolism, Dihydroxyphenylalanine metabolism, Dopamine biosynthesis, Mice, Piperidines chemical synthesis, Rats, Structure-Activity Relationship, Piperidines pharmacology, Receptors, Dopamine drug effects
- Abstract
In an attempt to enhance the potency of the dopamine autoreceptor agonist 3-PPP, racemic cis-3-(3-hydroxyphenyl)-5-[(methylmercapto)methyl]-N-n-propylpiperidine has been prepared in a stereoselective synthesis. NMR studies of 3 show a diequatorial conformation for the 3- and 5-substituents, which gives compound 3 an intriguing overlap with the ergoline derivative pergolide. Pharmacological testing revealed that 3, which is a 5-(methylmercapto)methyl derivative of racemic 3-PPP does not show the anticipated potency increase as a dopamine autoreceptor agonist. In vitro (inhibition of tyrosine hydroxylation) 3 and 1 have similar potency, and the in vivo potency (inhibition of GBL accelerated dopamine synthesis) of 3 is inferior to that of 1.
- Published
- 1985
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20. Blockade of heart 3H-norepinephrine up-take by 4-phenyl-1-aminotetralines: implications for the active conformation of imipramine-like drugs.
- Author
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Sarges R, Koe BK, Weissman A, and Schaefer JP
- Subjects
- Amines administration & dosage, Amines pharmacology, Animals, Body Temperature drug effects, Crystallography, Depression, Chemical, Desipramine pharmacology, Dose-Response Relationship, Drug, Male, Mice, Molecular Conformation, Naphthalenes administration & dosage, Norepinephrine antagonists & inhibitors, Rats, Reserpine antagonists & inhibitors, Reserpine pharmacology, Stereoisomerism, Structure-Activity Relationship, Time Factors, Tritium, Imipramine, Myocardium metabolism, Naphthalenes pharmacology, Norepinephrine metabolism
- Published
- 1974
21. Dopamine receptor blockade by imidoline and its proposed active conformation.
- Author
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Koe BK, Koch SW, and Dominy BW
- Subjects
- 3,4-Dihydroxyphenylacetic Acid metabolism, Adenylyl Cyclase Inhibitors, Animals, Binding Sites, Chlorpromazine pharmacology, Male, Molecular Conformation, Rats, Spiperone metabolism, Structure-Activity Relationship, Antipsychotic Agents pharmacology, Imidazoles pharmacology, Receptors, Dopamine drug effects
- Abstract
Imidoline, 1-[2-(N,N-dimethylamino)ethyl]-3-m-chlorophenyl-2-imidazolidinone, has been found to be as potent as chlorpromazine in increasing striatal DOPA accumulation and prolactin secretion in vivo. In contrast, imidoline exhibited only weak inhibitory activity towards dopamine-sensitive adenylate cyclase and 3H-spiroperidol binding to striatal membranes in vitro. These neuroleptic effects in vivo are probably caused by blockade of dopamine receptors since imidoline did not deplete the striatum of dopamine. Imidoline is of interest because its structure is distinct from those of other neuroleptics. A proposed active conformation involves intramolecular hydrogen bonding between the protonated dimethylamino group and the oxygen of the imidazolidinone ring. The spatial relationship between the amine nitrogen and phenyl ring in this conformation allows proper fit of imidoline with key dimensions described for the dopamine receptor.
- Published
- 1980
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22. Differential effects of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) at dopamine receptor sites.
- Author
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Koch SW, Koe BK, and Bacopoulos NG
- Subjects
- 3,4-Dihydroxyphenylacetic Acid analysis, Animals, Apomorphine pharmacology, Dopamine pharmacology, Homovanillic Acid analysis, Male, Mice, Molecular Conformation, Rats, Rats, Inbred Strains, Stereoisomerism, Synaptosomes drug effects, Tyrosine 3-Monooxygenase antagonists & inhibitors, Corpus Striatum drug effects, Piperidines pharmacology, Receptors, Dopamine drug effects
- Abstract
The agonist actions of 3-PPP at central dopamine (DA) autoreceptors were found to reside mostly in its (+) enantiomer, (+)-3-PPP also reduced striatal content of DOPAC and HVA, whereas (-)-3-PPP elevated HVA levels. Only (-)-3-PPP antagonized DA stimulation of DA-receptor linked adenylate cyclase. It was more effective than (+)-3-PPP at inhibiting [3H]DA binding to striatal membranes. The results suggest that (+)-3-PPP may act predominantly at DA autoreceptors, while (-)-3-PPP exhibits weak affinity for presynaptic and postsynaptic DA receptors.
- Published
- 1983
- Full Text
- View/download PDF
23. Pharmacology of sertraline: a review.
- Author
-
Heym J and Koe BK
- Subjects
- 1-Naphthylamine analogs & derivatives, 1-Naphthylamine therapeutic use, Animals, Behavior, Animal drug effects, Body Weight drug effects, Depressive Disorder drug therapy, Humans, Obsessive-Compulsive Disorder drug therapy, Rats, Serotonin Antagonists therapeutic use, Sertraline, 1-Naphthylamine pharmacology, Naphthalenes pharmacology, Serotonin Antagonists pharmacology
- Abstract
Sertraline is a member of a new class of psychotherapeutic agents that selectively inhibit serotonin reuptake in the brain. Animal studies have demonstrated that inhibition of serotonin reuptake leads to enhanced serotonergic neurotransmission and indirectly results in a down-regulation of beta-adrenoceptors. The preclinical pharmacology of sertraline predicts antidepressant activity without accompanying anticholinergic, cardiotonic, or sedative side effects. Recent laboratory and clinical observations pertaining to body weight and obsessive compulsive disorder suggest the possibility of broader clinical indications for selective serotonin reuptake blockers such as sertraline.
- Published
- 1988
24. Treatment with sertraline, a new serotonin uptake inhibitor, reduces voluntary ethanol consumption in rats.
- Author
-
Gill K, Amit Z, and Koe BK
- Subjects
- 1-Naphthylamine analogs & derivatives, Animals, Drinking drug effects, Male, Rats, Rats, Inbred Strains, Saccharin, Sertraline, Solutions, Time Factors, Volition, 1-Naphthylamine pharmacology, Alcohol Drinking drug effects, Naphthalenes pharmacology, Serotonin Antagonists metabolism
- Abstract
Serotonin uptake blockers have been shown to produce a robust and reliable reduction in voluntary ethanol consumption in rats. These compounds are currently under investigation as potential treatments for alcohol abuse in humans. It is uncertain whether serotonin uptake blockers exert their effects directly through serotonergic mechanisms or whether an interaction between the serotonin and noradrenergic systems is involved. The present series of experiments was designed to examine the effects of sertraline, a new selective serotonin uptake blocker, on voluntary ethanol intake. Sertraline produced a robust reduction in voluntary ethanol intake. It appears therefore, that increasing selectivity for serotonin blockade does not alter the efficacy of these compounds as antialcohol agents. The drug also reduced the consumption of a saccharin solution indicating that sertraline's effects are not specific to ethanol intake.
- Published
- 1988
- Full Text
- View/download PDF
25. Sertraline, a selective inhibitor of serotonin uptake, induces subsensitivity of beta-adrenoceptor system of rat brain.
- Author
-
Koe BK, Koch SW, Lebel LA, Minor KW, and Page MG
- Subjects
- 1-Naphthylamine analogs & derivatives, Adenylyl Cyclases metabolism, Animals, Brain metabolism, Dihydroalprenolol metabolism, Male, Quipazine pharmacology, Rats, Rats, Inbred Strains, Receptors, Adrenergic drug effects, Serotonin Antagonists pharmacology, Sertraline, 1-Naphthylamine pharmacology, Brain drug effects, Naphthalenes pharmacology, Receptors, Adrenergic, beta drug effects
- Abstract
Subacute administration (b.i.d. for 4 days) of sertraline, a potent and selective inhibitor of serotonin uptake, was found to reduce cyclic AMP generation by the norepinephrine receptor-coupled adenylate cyclase in rat limbic forebrain slices and decrease the number of beta-adrenoceptors in rat cerebral cortex without affecting the affinity of [3H]dihydroalprenolol binding. Co-administration of sertraline and the serotonin agonist, quipazine, at doses at which neither agent had an effect, resulted in desensitization of norepinephrine receptor-coupled adenylate cyclase and down-regulation of beta-adrenoceptors. These findings suggest that increased serotonergic activity may be involved in the induction of subsensitivity of the beta-adrenoceptor system of rat brain by sertraline.
- Published
- 1987
- Full Text
- View/download PDF
26. Contrasting effects of ethyl beta-carboline-3-carboxylate (beta CCE) and diazepam on cerebellar cyclic GMP content and antagonism of both effects by Ro 15-1788, a specific benzodiazepine receptor blocker.
- Author
-
Koe BK and Lebel LA
- Subjects
- Animals, Carbolines antagonists & inhibitors, Cerebellum drug effects, Diazepam antagonists & inhibitors, Flumazenil, In Vitro Techniques, Isoniazid pharmacology, Male, Rats, Rats, Inbred Strains, Receptors, Cell Surface drug effects, Receptors, GABA-A, Benzodiazepinones pharmacology, Carbolines pharmacology, Cerebellum metabolism, Cyclic GMP metabolism, Diazepam pharmacology, Indoles pharmacology
- Abstract
Ethyl beta-carboline-3-carboxylate (beta CCE), a benzodiazepine antagonist, was found to increase basal levels of cyclic GMP in rat cerebellum. beta CCE also augmented the elevation of cyclic GMP concentrations induced by isoniazid, in contrast to diazepam which blocked this effect of isoniazid. Administration of beta CCE and diazepam together cancelled each other's effect on the elevation of cyclic GMP levels after isoniazid. Ro 15-1788, another potent benzodiazepine antagonist, was found to have virtually no effect on cyclic GMP levels in naive or isoniazid-treated rats. Ro 15-1788 antagonized diazepam's lowering of the elevation of cyclic GMP content of cerebellum after isoniazid. Ro 15-1788 also blocked the increase in cyclic GMP levels elicited by beta CCE, indicating that this effect of beta CCE involves its interaction at benzodiazepine receptors. Some pharmacological actions of beta CCE might be based on hindering GABA transmission.
- Published
- 1983
- Full Text
- View/download PDF
27. Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines.
- Author
-
Harbert CA, Plattner JJ, Welch WM, Weissman A, and Koe BK
- Subjects
- Animals, Binding, Competitive, Carbolines metabolism, Carbolines pharmacology, Corpus Striatum metabolism, Dextroamphetamine antagonists & inhibitors, Humans, In Vitro Techniques, Male, Rats, Receptors, Dopamine metabolism, Solubility, Spiperone metabolism, Stereotyped Behavior drug effects, Structure-Activity Relationship, Time Factors, Antipsychotic Agents chemical synthesis, Carbolines chemical synthesis, Indoles chemical synthesis
- Abstract
A series of 5-aryltetrahydro-gamma-carbolines was prepared by a novel N-arylation procedure and tested for neuroleptic activity in a rat antiamphetamine model. The systematic exploration of structural parameters leading to 8-fluoro-5-(4-fluorophenyl)-2-[4-hydroxy-4-(4-fluorophenyl)butyl]-2,3,5-tetrahydro-1H-pyrido[4,3-b]indole (CP-36,584, flutroline), a potent and long-acting neuroleptic compound, is described. These semirigid compounds provide a new, structurally distinct series with which to probe the conformational requirements for potent activity at the dopamine receptor.
- Published
- 1980
- Full Text
- View/download PDF
28. Stereospecific and potent analgetic activity for nantradol--a structurally novel, cannabinoid-related analgetic.
- Author
-
Milne GM, Koe BK, and Johnson MR
- Subjects
- Analgesics, Animals, Cannabinoids, Chemical Phenomena, Chemistry, Male, Mice, Phenanthridines pharmacology
- Published
- 1979
29. Inhibition of rat brain tryptophan hydroxylation with p-chloroamphetamine.
- Author
-
Koe BK and Corkey RF Jr
- Subjects
- Animals, Brain metabolism, Brain Stem enzymology, Corpus Striatum enzymology, Dihydroxyphenylalanine metabolism, Dopamine metabolism, Kinetics, Male, Rats, Amphetamines pharmacology, Brain enzymology, Mixed Function Oxygenases antagonists & inhibitors, Tryptophan Hydroxylase antagonists & inhibitors, p-Chloroamphetamine pharmacology
- Published
- 1976
- Full Text
- View/download PDF
30. Monoamine oxidase inhibitors antagonize the acceleration of brain dopamine synthesis induced by neuroleptic drugs in vivo: implications for the treatment of Tardive dyskinesia.
- Author
-
Koe BK
- Subjects
- Animals, Corpus Striatum metabolism, Hydrazines pharmacology, Male, Movement Disorders drug therapy, Pargyline pharmacology, Rats, Tetrabenazine pharmacology, Tranquilizing Agents pharmacology, Trifluoperazine pharmacology, Brain drug effects, Dopamine biosynthesis, Monoamine Oxidase Inhibitors pharmacology, Tranquilizing Agents antagonists & inhibitors
- Published
- 1975
- Full Text
- View/download PDF
31. A novel class of "GABAergic" agents: 1-aryl-3-(aminoalkylidene)oxindoles.
- Author
-
Sarges R, Howard HR, Koe BK, and Weissman A
- Subjects
- Animals, Flunitrazepam metabolism, Male, Mice, Structure-Activity Relationship, 3-Mercaptopropionic Acid antagonists & inhibitors, Indoles pharmacology, Receptors, GABA-A drug effects, Sulfhydryl Compounds antagonists & inhibitors
- Abstract
Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles. Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dimethylamino)-ethylidene and N-methyl-2-pyrrolidinylidene side chains. The precise mechanism of action of these agents is unclear at this time; however, they are not GABA mimics and they do not affect GABA levels. Like other GABAergic agents, these compounds are potent enhancers of benzodiazepine binding and they antagonize cyclic GMP elevations induced by isoniazid. Compounds from this series may therefore have potential therapeutic utility as anticonvulsants or anxiolytics.
- Published
- 1989
- Full Text
- View/download PDF
32. Neuroleptic activity of chiral trans-hexahydro-gamma-carbolines.
- Author
-
Sarges R, Howard HR, Donahue KM, Welch WM, Dominy BW, Weissman A, Koe BK, and Bordner J
- Subjects
- Animals, Chemical Phenomena, Chemistry, Dextroamphetamine antagonists & inhibitors, Male, Mice, Molecular Conformation, Rats, Rats, Inbred Strains, Receptors, Dopamine drug effects, Spiperone metabolism, Stereoisomerism, Structure-Activity Relationship, Carbolines pharmacology, Receptors, Dopamine metabolism, Stereotyped Behavior drug effects
- Abstract
A series of trans-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5, 9b-hexahydro-1H-pyrido[4,3-b]indoles with various N-2 substituents has been prepared and tested for neuroleptic activity [( 3H]spiroperidol binding and amphetamine antagonism). Several members of this series showed exceptional in vivo potency, especially the hydantoin derivatives 27-30. Resolution into the enantiomers showed that neuroleptic activity is associated with the 4aS,9bS absolute configuration. These rigid neuroleptics have been correlated with other rigid neuroleptics [(+)-dexclamol, Ro 22-1319] and can serve to further define the topography of the dopamine receptor.
- Published
- 1986
- Full Text
- View/download PDF
33. Neuroleptics from the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole series. 3. Carboxamidoalkyl derivatives.
- Author
-
Welch WM, Harbert CA, Sarges R, Weissman A, and Koe BK
- Subjects
- Animals, Antipsychotic Agents pharmacology, Carbolines pharmacology, Hydrogen Bonding, Rats, Receptors, Dopamine drug effects, Structure-Activity Relationship, Antipsychotic Agents chemical synthesis, Carbolines chemical synthesis
- Abstract
Substitution of position 2 of the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole nucleus with omega-carboxamidoalkyl substituents leads to compounds with exceedingly potent neuroleptic activity in in vitro and in vivo models. Although duration of activity is not as long as that of the analogous 4-hydroxy-4-(4-fluorophenyl)butyl derivatives reported previously, the absolute potency in vivo is greater. The ability of these compounds to bind with great affinity to dopamine (DA) receptors further defines the nature of the DA receptor auxiliary binding site as a hydrogen-bond donating site in addition to or instead of a lipophilic site as has been previously proposed.
- Published
- 1986
- Full Text
- View/download PDF
34. [3H]Ro 15-1788 binding to benzodiazepine receptors in mouse brain in vivo: marked enhancement by GABA agonists and other CNS drugs.
- Author
-
Koe BK, Kondratas E, and Russo LL
- Subjects
- Animals, Antipsychotic Agents pharmacology, Barbiturates metabolism, Brain drug effects, Buspirone pharmacology, Flunitrazepam metabolism, In Vitro Techniques, Injections, Intravenous, Male, Mice, Picrotoxin metabolism, Rats, Rats, Inbred Strains, Receptors, GABA-A drug effects, Vasodilator Agents, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid pharmacology, Brain metabolism, Flumazenil metabolism, Receptors, GABA-A metabolism, gamma-Aminobutyric Acid physiology
- Abstract
Administration of the benzodiazepine receptor antagonist, [3H]Ro 15-1788, to mice intravenously was found to label these receptors in brain. Binding of [3H]Ro 15-1788 in vivo was strongly blocked by pretreating mice with clonazepam or diazepam. Marked enhancement of [3H]Ro 15-1788 binding in vivo was induced by progabide or sodium valproate. This effect was greater than a similar enhancement of [3H]flunitrazepam binding. The increased membrane-bound [3H]Ro 15-1788 elicited by progabide was completely dissociated on subsequent incubation with Ro 15-1788, diazepam or clobazam, indicating that the enhanced binding occurred at benzodiazepine receptors. Compounds that exert diazepam-like actions and/or indirect GABAergic activity (cartazolate, pentobarbital, methaqualone, levonantradol, phenytoin) elicited enhancement of [3H]Ro 15-1788 in vivo. Other CNS agents (atypical neuroleptics, GABA antagonists, baclofen, some 5-HT1 agonists) also induced elevation of [3H]Ro 15-1788 binding in vivo, as did drugs exerting vasodilatatory effects (papaverine, nimodipine, verapamil, prazosin, N6-cyclohexyladenosine). Possible explanations for enhancement of [3H]Ro 15-1788 binding in vivo include increase in the number of benzodiazepine receptors induced by GABA or GABAergic drugs or effects of binding enhancers that elevate brain levels of [3H]Ro 15-1788, such as accelerating cerebral blood flow, competing for radioligand binding sites in plasma or increasing metabolic stability of the radioligand.
- Published
- 1987
- Full Text
- View/download PDF
35. GABA-like actions of levonantradol.
- Author
-
Leader JP, Koe BK, and Weissman A
- Subjects
- 3-Mercaptopropionic Acid antagonists & inhibitors, Animals, Cerebellum metabolism, Cyclic GMP metabolism, Dihydroxyphenylalanine metabolism, Haloperidol antagonists & inhibitors, Male, Rats, Rats, Inbred Strains, Seizures chemically induced, Stereoisomerism, gamma-Aminobutyric Acid metabolism, Phenanthridines pharmacology, gamma-Aminobutyric Acid pharmacology
- Abstract
The interaction of levonantradol and its pharmacologically less active (+)-enantiomer with GABAergic mechanisms was studied in several in vivo systems: (1) rat cerebellar cGMP, based on the inverse relationship of GABAergic activity and cGMP levels; (2) convulsions elicited by 3-mercaptopropionic acid, an inhibitor of GABA synthesis; and (3) activated dopamine synthesis in rat striatum following blockade of dopamine receptors. Levonantradol decreased rat cerebellar cGMP content at low doses (1.0 mg/kg intraperitoneally) and antagonized elevation of cGMP levels by the GABA biosynthesis inhibitor isoniazid at even lower doses (0.32 mg/kg intraperitoneally); this activity pattern is suggestive of GABAergic activity. This conclusion is also supported by levonantradol's protection of mice against the convulsant effects of 3-mercaptopropionic acid, GABAergic agents are known to antagonize the enhanced dopamine synthesis and turnover that accompany dopamine receptor blockade by neuroleptics. Levonantradol (0.047 mg/kg intravenously) stereospecifically attenuated the elevated dopa accumulation induced by haloperidol. Levonantradol is at least 100-fold more active than THC in blocking isoniazid-induced elevation of cGMP levels in rat cerebellum or haloperidol-induced enhanced dopa accumulation in rat striatum.
- Published
- 1981
- Full Text
- View/download PDF
36. Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain.
- Author
-
Koe BK
- Subjects
- Animals, Brain metabolism, Butylamines pharmacology, Depression, Chemical, Dopamine metabolism, In Vitro Techniques, Male, Molecular Conformation, Norepinephrine metabolism, Phenethylamines pharmacology, Propylamines pharmacology, Rats, Amines pharmacology, Brain ultrastructure, Catecholamines metabolism, Serotonin metabolism, Synaptosomes metabolism
- Abstract
Several compounds of relatively rigid molecular structure have been found to exert strong blockade of monoamine uptake by synaptosomal preparations of rat corpus striatum (dopamine and serotonin) and hypothalamus (norepinephrine). These include CP-24,441 (1R, 4S-N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine), EXP-561 (4-phenylbicyclo[2.2.2]octan-1-amine), nomifensine and nefopam. The well-defined molecular geometry of the potent inhibitor EXP-561 is a fundamental structural/conformational requirement for uptake blocking activity for the large family of phenylbutylamine- and phenoxypropylamine-related inhibitors. The tubular configuration of EXP-561 may be the most appropriate for blocking serotonin uptake. The requisite conformation for blocking dopamine uptake appears to be defined by the combination resulting from superimposition of the CP-24,441 and nomifensine structures. The conformation defined by the combination resulting from superimposition of the CP-24-441 and desipramine structures is apparently optimal for blocking norepinephrine uptake. The conformational requirements for diphenylpropylamine-related uptake blockers may be defined by the rigid compound CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2-naphthylamine). The actual potency of any given inhibitor is probably modulated by additional structural and stereochemical factors.
- Published
- 1976
37. Blockade of hepatic aldehyde dehydrogenase in mice on chronic ingestion of 4-bromopyrazole and 4-iodopyrazole.
- Author
-
Koe BK and Tenen SS
- Subjects
- Acetaldehyde blood, Alcohol Drinking drug effects, Animals, Bromine, Ethanol blood, Iodine, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Time Factors, Aldehyde Oxidoreductases antagonists & inhibitors, Liver enzymology, Pyrazoles pharmacology
- Published
- 1975
- Full Text
- View/download PDF
38. 4a,9b-trans-8-Fluoro-5-(4-fluorophenyl)-2-[4-(4-fluorophenyl)-4-hydroxybutyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride, a new potent neuroleptic.
- Author
-
Welch WM, Ewing FE, Harbert CA, Weissman A, and Koe BK
- Subjects
- Animals, Carbolines pharmacology, Dextroamphetamine antagonists & inhibitors, Humans, In Vitro Techniques, Models, Molecular, Rats, Receptors, Dopamine drug effects, Stereoisomerism, Stereotyped Behavior drug effects, Antipsychotic Agents chemical synthesis, Carbolines chemical synthesis, Indoles chemical synthesis
- Abstract
The preparation and testing of the two racemic diastereoisomers and the four optically active enantiomers of the title compound in in vitro and in vivo models for determining potential antipsychotic activity are described. Both racemic diastereoisomers and two of the four chiral enantiomers are potent and long-acting neuroleptic compounds.
- Published
- 1980
- Full Text
- View/download PDF
39. Neuroleptic activity of the 5-aryltetrahydro-gamma-carboline series. Conformational requirements for interaction with central dopamine receptors.
- Author
-
Harbert CA, Plattner JJ, Welch WM, Weissman A, and Koe BK
- Subjects
- Amphetamine antagonists & inhibitors, Animals, Binding Sites, Carbolines metabolism, Humans, In Vitro Techniques, Male, Molecular Conformation, Rats, Spiperone metabolism, Stereotyped Behavior drug effects, Structure-Activity Relationship, Antipsychotic Agents pharmacology, Carbolines pharmacology, Indoles pharmacology, Receptors, Dopamine drug effects
- Published
- 1980
40. Facilitation of benzodiazepine binding by levonantradol.
- Author
-
Koe BK and Weissman A
- Subjects
- Animals, Anti-Anxiety Agents pharmacology, Brain drug effects, Brain metabolism, Diazepam metabolism, Drug Interactions, Flunitrazepam metabolism, Male, Mice, Pentylenetetrazole antagonists & inhibitors, Rats, Stereoisomerism, Anti-Anxiety Agents metabolism, Phenanthridines pharmacology
- Abstract
Levonantradol enhanced binding of 3H-diazepam to rat cortical membranes. Scatchard analysis of this effect showed apparent KD and Bmax changes at 100 microM levonantradol and a KD decrease at 50 microM. Dextronantradol caused a similar enhancement, suggesting a lack of stereospecificity in vitro. Subsequently, levonantradol at pharmacologic doses (0.15 mg/kg subcutaneously) was found to enhance the binding of intravenous 3H-flunitrazepam to mouse brain. In contrast to the results in vitro, dextronantradol showed no enhancement of 3H-flunitrazepam binding at doses up to 15 mg/kg subcutaneously. This stereospecific interaction with benzodiazepine receptors in vivo suggests that levonantradol may facilitate the pharmacologic actions of benzodiazepines. Levonantradol, at doses of 0.32 and 3.2 mg/kg subcutaneously, which did not block the convulsant effect of pentylenetetrazol, enhanced both the potency and efficacy of diazepam in elevating the absolute threshold of pentylenetetrazol for eliciting clonic seizures. Consistent with its lack of facilitation of benzodiazepine binding, dextronantradol at 3.2 mg/kg, a dose without effect on pentylenetetrazol-induced convulsions, showed little or no enhancement of diazepam's anticonvulsant activity against the latter.
- Published
- 1981
- Full Text
- View/download PDF
41. Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins.
- Author
-
Welch WM, Kraska AR, Sarges R, and Koe BK
- Subjects
- Animals, Dopamine metabolism, Isomerism, Male, Norepinephrine metabolism, Rats, Rats, Inbred Strains, Serotonin metabolism, Stereoisomerism, Synaptosomes metabolism, Tetrahydronaphthalenes pharmacology, X-Ray Diffraction, Antidepressive Agents chemical synthesis, Naphthalenes chemical synthesis, Tetrahydronaphthalenes chemical synthesis
- Abstract
The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of depression has long been suspected and has given impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake. This paper presents structure-activity relationships for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models. These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine. The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.
- Published
- 1984
- Full Text
- View/download PDF
42. Sertraline potently displaces (+)-[3H]3-PPP binding to sigma sites in rat brain.
- Author
-
Schmidt A, Lebel L, Koe BK, Seeger T, and Heym J
- Subjects
- 1-Naphthylamine analogs & derivatives, Animals, Binding, Competitive drug effects, In Vitro Techniques, Rats, Receptors, Opioid, delta, Sertraline, 1-Naphthylamine pharmacology, Brain Chemistry drug effects, Naphthalenes pharmacology, Piperidines metabolism, Receptors, Opioid metabolism, Serotonin Antagonists pharmacology
- Published
- 1989
- Full Text
- View/download PDF
43. Neuroleptics from the 4a,9b-cis- and 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole series. 2.
- Author
-
Welch WM, Harbert CA, Weissman A, and Koe BK
- Subjects
- Animals, Antipsychotic Agents pharmacology, Carbolines pharmacology, Hydrogen Bonding, Molecular Conformation, Rats, Receptors, Dopamine drug effects, Structure-Activity Relationship, Antipsychotic Agents chemical synthesis, Carbolines chemical synthesis
- Abstract
Compounds derived from 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4, 3-b]indole are consistently efficacious in displacing [3H]spiroperidol from striatal dopamine receptors in vitro. Derivatives bearing substituents at position 2, particularly those derived from butyrophenone moieties, are exceptionally potent in vivo. Compounds from the corresponding 4a,9b-cis series are substantially less potent in both in vivo and in vitro assays of neuroleptic activity. Although the cis and trans derivatives have, in some conformations, similar basic nitrogen atom to aromatic ring separations of about 5.1 A, the distance at which the basic nitrogen atom lies above or below the plane of the aromatic ring differs substantially between the two series. Consideration of these results in terms of this and earlier work indicates that the out-of-plane distance for the basic nitrogen in neuroleptic molecules may range from about 0 to about 0.90 A but may be optimized at about 0.55 A.
- Published
- 1986
- Full Text
- View/download PDF
44. Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics.
- Author
-
Koe BK, Milne GM, Weissman A, Johnson MR, and Melvin LS
- Subjects
- Animals, Anticonvulsants pharmacology, Calcium metabolism, Cerebellum analysis, Cyclic GMP analysis, Diazepam pharmacology, Male, Mice, Rats, Rats, Inbred Strains, Receptors, GABA-A drug effects, Tritium, Analgesics pharmacology, Brain metabolism, Cannabinoids pharmacology, Dronabinol pharmacology, Flunitrazepam metabolism
- Abstract
Novel, synthetic cannabimimetics and delta 9-tetrahydrocannabinol were found to enhance the binding of [3H]flunitrazepam to mouse brain in vivo. This property, suggestive of facilitation of binding to benzodiazepine receptors, is consistent with the potentiation of the anticonvulsant activity of diazepam against pentylenetetrazol by these compounds. The relative potencies of delta 9-tetrahydrocannabinol and the new cannabimimetics for enhancing [3H]flunitrazepam binding in vivo could also be correlated with their relative analgesic efficacies. Similar pharmacological stereospecificity was displayed for both binding enhancement and analgesic effects. The following order of decreasing potency was observed: N-methyllevonantradol and (-)-CP-55,244 greater than levonantradol, canbisol, CP-42,096 and (-)-CP-55,940 greater than 9-beta-normethyl-9-beta-hydroxyhexahydrocannabinol, nabilone and CP-47,497 greater than delta 9-tetrahydrocannabinol. Dextronantradol, (+)-CP-55,940 and (+)-CP-55,244 were considerably less active than the respective (-)-enantiomers; cannabidiol was inactive. Extensive investigation of structure versus activity led to N-methyllevonantradol and the 3-(2-hydroxyphenyl)cyclohexanols derivative, (-)-CP-55,244, which are approximately 1000-fold more potent than delta 9-tetrahydrocannabinol.
- Published
- 1985
- Full Text
- View/download PDF
45. (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine binding to sigma receptors in mouse brain in vivo.
- Author
-
Koe BK, Burkhart CA, and Lebel LA
- Subjects
- Animals, Dose-Response Relationship, Drug, Mice, Rats, Receptors, Opioid, delta, Time Factors, Brain Chemistry drug effects, Dopamine Agents pharmacology, Piperidines pharmacology, Receptors, Opioid metabolism
- Abstract
Binding of i.v. administered (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]3-PPP) in the brain of intact mice is antagonized dose responsively by sigma receptor ligands. The correlation of potencies for inhibition of binding in vivo and in vitro indicates that sigma receptors in mouse brain are labeled in vivo by i.v. [3H]3-PPP. 3-PPPP, the N-phenylpropyl derivative of norpropyl-3-PPP exhibits very high affinity for sigma receptors in vitro and in vivo.
- Published
- 1989
- Full Text
- View/download PDF
46. In vitro conversion of phytofluene and phytoene into carotenoid pigments.
- Author
-
KOE BK and ZECHMEISTER L
- Subjects
- Humans, In Vitro Techniques, Biological Products, Carotenoids, Pigments, Biological, Vitamin A
- Published
- 1952
- Full Text
- View/download PDF
47. PREPARATION AND ANTIBIOTIC PROPERTIES OF SOME PHOSPHINYLAMINOPENICILLANIC ACIDS AND PHOSPHINOTHIOYLAMINOPENICILLANIC ACIDS.
- Author
-
KOE BK, SETO TA, ENGLISH AR, and MCBRIDE TJ
- Subjects
- Mice, Anti-Bacterial Agents, Chemistry, Pharmaceutical, Drug Resistance, Drug Resistance, Microbial, Penicillinase, Penicillins, Pharmacology, Phosphinic Acids, Research, Staphylococcal Infections, Staphylococcus
- Published
- 1963
- Full Text
- View/download PDF
48. The pharmacology of para-chlorophenylalanine, a selective depletor of serotonin stores.
- Author
-
Koe BK and Weissman A
- Subjects
- Animals, Behavior, Animal drug effects, Body Temperature drug effects, Brain drug effects, Brain metabolism, Dogs, Haplorhini, Humans, Liver enzymology, Male, Mixed Function Oxygenases metabolism, Norepinephrine metabolism, Pargyline pharmacology, Phenylketonurias chemically induced, Rats, Serotonin blood, Sleep drug effects, Spleen metabolism, Tryptophan, Phenylalanine pharmacology, Serotonin metabolism
- Published
- 1968
- Full Text
- View/download PDF
49. Pa 150, PA 153, and PA 166: new polyene antifungal antibiotics.
- Author
-
KOE BK, TANNER FW Jr, RAO KV, SOBIN BA, and CELMER WD
- Subjects
- Antifungal Agents, Fungicides, Industrial, Polyenes
- Published
- 1957
50. ISOLATION AND CHARACTERIZATION OF URINARY METABOLITES OF BENZQUINAMIDE AND BENZQUINAMIDE ALCOHOL.
- Author
-
KOE BK and PINSON R Jr
- Subjects
- Animals, Dogs, Chromatography, Ethanol, Glucuronidase, Metabolism, Quinolizines, Research, Tranquilizing Agents, Urine
- Published
- 1964
- Full Text
- View/download PDF
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