A novel electromagnetic apparatus for synchrotron X-ray imaging study of the separation of phases in metal solidification.

As a part of a research into new techniques for purifying recycled aluminium alloys, a novel electromagnetic apparatus had been developed for investigating in real-time the separation mechanisms of detrimental inclusions in aluminium alloy melts under alternating magnetic fields. The magnetic coil was designed based on the Helmholtz coil design. A viewing gap was designed for imaging studies using synchrotron X-rays.

A case of primary adrenal gland lymphoma.

Primary adrenal lymphoma is extremely rare. We describe a case of non-Hodgkin's lymphoma of diffuse large B-cell type with right adrenal involvement. The patient received chemotherapy and external irradiation and achieved complete remission of the disease.

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.

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.

Characterization of [3H]CP-96,501 as a selective radioligand for the serotonin 5-HT1B receptor: binding studies in rat brain membranes.

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.

Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.

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.

Structure-activity relationship of quinazolinedione inhibitors of calcium-independent phosphodiesterase.

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.

Nicotinamide ethers: novel inhibitors of calcium-independent phosphodiesterase and [3H]rolipram binding.

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.

Calcium-independent phosphodiesterase inhibitors as putative antidepressants: [3-(bicycloalkyloxy)-4-methoxyphenyl]-2-imidazolidinones.

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.

Preclinical pharmacology of sertraline: a potent and specific inhibitor of serotonin reuptake.

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.

4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants.

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.

[3H] sertraline binding to rat brain membranes.

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.

(+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine binding to sigma receptors in mouse brain in vivo.

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.

A novel class of "GABAergic" agents: 1-aryl-3-(aminoalkylidene)oxindoles.

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.

Treatment with sertraline, a new serotonin uptake inhibitor, reduces voluntary ethanol consumption in rats.

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.

Pharmacology of sertraline: a review.

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.

[3H]Ro 15-1788 binding to benzodiazepine receptors in mouse brain in vivo: marked enhancement by GABA agonists and other CNS drugs.

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.

Sertraline, a selective inhibitor of serotonin uptake, induces subsensitivity of beta-adrenoceptor system of rat brain.

Subacute administration (b.i.d.

Neuroleptics from the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole series. 3. Carboxamidoalkyl derivatives.

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.

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.

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.

Neuroleptic activity of chiral trans-hexahydro-gamma-carbolines.

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.

Synthesis and dopamine autoreceptor activity of a 5-(methylmercapto)methyl-substituted derivative of (+/-)-3-PPP (3-(3-hydroxyphenyl)-1-n-propylpiperidine).

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.