bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nomifensine enantiomers: Psychopharmacological effects in mice and rats in comparison with D,L‐nomifensine
Authors: Kruse Hansjoerg , Scholtholt J. 
Published: January 2005

AbstractThe D‐ and L‐enantiomers of nomifensine (8‐amino‐2‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydrois‐oquinoline) were tested for psychopharmacological effects in mice and rats with D,L‐nomifensine hydrogen maleate as a reference drug. In tests on antidepressant activity (antagonism of tetrabenazine ptosis, reserpine hypothermia, oxotremorine hypothermia, “behavioral despair,” and potentiation of yohimbine toxicity), the D‐enantiomer was on average 1.7 or 2.8 times more potent than the racemate with the intraperitoneal (i.p.) or oral route of administration, respectively. The L‐enantiomer displayed slight ativity only when injected i.p. and was on average ≥ 30 times less potent than the racemate. In tests on dopaminergic acivity, D‐nomifensine was about 3 times (motor stimulation in mice) or 1.5–1.9 times (induction of stereotyped behavior in rats) more potent than the racemate. The L‐enantiomer was devoid of stimulant or stereotypic activity and had a rather sedative effect. In acute (24 h) toxicity studies, D‐nomifensine proved 2.9 or 4.5 times more toxic, and L‐nomifensine was 1.6 or 1.3 times less toxic than the racemate (i.p. or p.o., respectively). The results indicate that nomifensine acts by stereospecific mechanisms and that the D‐enantiomer is the active component.
Yohimbine‐induced seizures in mice: A model predictive of potential anxiolytic and GABA‐mimetic agents
Authors: Dunn Robert W. , Fielding Stuart 
Published: January 2005

AbstractYohimbine potentiation of lethality in mice has been used as a model for the prediction of antidepressant agent [Quinton, 1963]. However, prior to death or at sublethal doses, yohimbine induces clonic convulsions. In Swiss‐Webster mice (20–28 g) individually placed in clear plastic cylinders, the CD50 (median convulsive dose) for yohimbine‐induced seizures was 22.7 (18.9−27.3) mg/kg sc (subcutaneously). For anticonvulsant screening, compounds were administered intraperitoneally at appropriate pretreatment times prior to the CD95 dose of yohimbine (45 mg/kg sc). The following anxiolytic and GABA‐mimetic agents administered intraperitoneally dose‐dependently antagonized yohimbine‐induced clonic convulsions: diazepam (ED50) = 0.26 mg/kg); chlordiazepoxide (2.0 mg/kg); CGS 9896 (0.82 mg/kg); CL 218,872 (3.7 mg/kg); zopiclone (19.0 mg/kg); tracazolate (61.3 mg/kg); clonazepam (0.02 mg/kg); phenobarbital (9.0 mg/kg); valproic acid (81.1 mg/kg); trimethadione (163.0 mg /kg); muscimol (0.82 mg/kg); AOAA (16.0 mg/kg); clonidine (0.22 mg/kg); and baclofen (4.0 mg/kg). On the other hand, the antiepileptic agents diphenylhydantoin, ethosuximide, and carbamazepine as well as the benzodiazepine antagonists CGS 8216 and RO 15 1788 were inactive. The neuroleptics haloperidol, chlorpromazine, and thioridazine were inactive, while clozapine displayed anticonvulsant activity (ED50 = 30.4 mg/kg). Other inactive compounds include phenotolamine, propranolol, atropine, alpha‐methyltyrosine, PCPA, reserpine, buspirone, DMI, and imipramine. Since yohimbine has been reported to be anxiogenic in animals and man, this assay may be relevant for the prediction of anxiolytic agents. Furthermore, compounds active in this test have shown anxiolytic activity in behavioral conflict paradigms.
Enzymic biomedical research and new drug development
Authors: Tegeler John J. , Kim Kwon H. 
Published: January 2005

AbstractThe proceedings of a symposium on current trends in enzyme‐guided biomedical research and its relation to potential new drug discovery are reviewed. Topics under discussion include current concepts in enzyme inhibition, the mechanism and inhibition of phopholipase A2, 5‐lipoxygenase and inflammation, the protease/antiprotease hypothesis of emphysema, carbonic anhydrase and glaucoma, GTP‐binding proteins and adenylate cyclase, and the calpain hypothesis of memory storage.
5‐Lipoxygenase, leukotrienes, and regulation of inflammatory responses
Authors: Parker Charles W. 
Published: January 2005

Abstract5‐Lipoxygenses are enzymes in leukocytes and mast cells that oxidize arachidonic acid to 5‐hydroperoxyeicosatetraenoic acid, which is in turn converted to a variety of products including leukotriene B4and the sulfidoleukotrienes (LTC4, LTD4and LTE4). These substances exert a broad range of biologic actions including effects on cell migration, enzyme secretion, smooth muscle contraction in the respiratory and gastrointestinal tracts, and vascular permeability. Considerable evidence now implicates these products in a variety of acute and chronic inflammatory responses in vivo as well as in acute allergic reactions affecting the airway and skin.
Interoceptive stimuli produced by cocaine are blocked during diazepam withdrawal
Authors: Wood Douglas M. , Ranschaert Erik R. , Lal Harbans 
Published: January 2005

AbstractRats were trained to select one lever after an intraperitoneal (ip) injection of cocaine (10 mg/kg), and an alternate lever after saline injection under a FR10 schedule of food reinforcement. Following chronic administration of cocaine (20 mg/kg/8hr), but not diazepam (80 mg/kg/8hr) for 7 days, the dose‐effect curve for the generalization of cocaine shifted twofold to the right. Subsequently, in the rats receiving chronic diazepam, RO 15‐1788, a drug known to precipitate diazepam withdrawal, failed to substitute for cocaine: however, the discriminability of cocaine (5 mg/kg) was reduced from 83% to 13% selection of cocaine‐appropriate lever after 72 hr following the last diazepam, injection. These data suggest that chronic administration of cocaine, but not diazepam, produced tolerance to the discriminative stimulus properties of cocaine, and following chronic diazepam administration and withdrawal, the stimulus properties of cocaine are antagonized.
Evaluation of oral skeletal muscle relaxants in the morphine‐induced straub tail test in mice
Authors: Pong Schwe Fang , Sweetman Janet Mary , Pong Amy Sue , Carpenter John Franklin 
Published: January 2005

AbstractMorphine is known to produce a characteristic and reproducible elevation of the tail in mice (Straub tail response). The morphine‐induced Straub tail response in mice has been used to evaluate skeletal muscle relaxant (SMR) activity of compounds administered intraperitoneally (i.p.). This model was used to evaluate the oral (p.o.) efficacy of a number of SMRs and other pharmacological agents. Male mice (n ≥ 5) were given test drugs p.o. followed by morphine sulfate [15 mg/kg subcutaneously (s.c.)] 15 min later. The mice were scored all or none for a Straub tail reaction 45 min later. Graded doses of active compounds were further evaluated for ED50 estimation by probit analysis. ED50 values (mg/kg) were estimated for the following compounds: baclofen (6.4), chlorpromazine HCl (3.8), cyclobenzaprine HCl (24.6), dantrolene Na (14.4), diazepam (8.3), haloperidol (6.2), naloxone HCl (8.7), phenoxybenzamine HCl (47.6), phentolamine HCl (265), and trifluoperazine HCl (25.4). These ED50 values appeared to correlate with initial adult human daily oral doses for muscle relaxation. The following compounds inhibited the Straub tail response in ≤ 40% of the mice tested at the doses indicated (mg/kg): carisoprodol (300), lidocaine (100), mephenesin (300), phenytoin (100), procainamide HCl (100), procaine HCl (100), propranolol HCl (100), quinidine sulfate (100); and all selected calcium‐channel blockers (30), antidepressants (30), and neuromuscular blocking agents (> 10 times the literature i.p. ED50 values with the exception of gallamine triethiodide at 30 mg/kg) that were tested. Pentobarbital Na was active only at doses that impaired the righting reflex. This animal model was thus determined to be useful for evaluating SMR efficacy and in predicting.
Preliminary analysis of the discriminative stimuli induced by the calcium channel “agonist” BAY K 8644
Authors: Gladstein Laura , Traber Jörg , Spencer David G. 
Published: January 2005

AbstractRats were trained in a drug discrimination paradigm to press one of two levers for food reward after injection of the racemic dihydropyridine (DHP) Ca2+ ‐channel activator BAY K 8644 (2.5 mg/kg) and to press the other after vehicle injection. The discrimination was reliably attained in an average of 48 sessions. Thereafter, tests with various doses of BAY K 8544 yielded a dose‐dependent selection of the BAY K 8644 lever, with an ED50 of 0.74 mg/kg. The (−)‐enantiomer of BAY K 8644 generalized dose‐dependently (ED50 = 1.04 mg/kg), while the (+)‐enantiomer showed no generalization up to 10 mg/kg. Furthermore, nifedipine pretreatment fully antagonized the BAY K 8644 stimulus. These data indicate that BAY K 8644 produces physiological effects that can readily serve as discriminative stimuli in rats. The results also support the mediation of the BAY K 8644 stimulus through agonistic interaction with the calcium channel DHP receptor.
Potential antipsychotic BMY 14802 selectively binds to sigma sites
Authors: Taylor Duncan P. , Dekleva Jennifer 
Published: January 2005

AbstractBMY 14802 presents a pharmacologic profile which, from behaviral testing, suggests potential as an antipsychotic agent with fewer side effects than currently available drugs. In marked contrast to these agents, BMY 14802 appears to have a “nondopaminergic” site of action. In view of the suggestion that antagonists of the so‐called s̀ site (labelled with high affinity by N‐allylnormetazocine and sensitive to haloperidol) may represent a new approach in the development of potential antipsychotic agents, we investigated the interaction of BMY 14802 with this site. We report that BMY 14802 selectively inhibited binding at this site, displaying stereospecificity, with the dextrorotatory form more potent than the levorotatory enatiomer, and that (+) BMY 14802 inhibited binding at this site in a competitive fashion.
General neuropharmacology of vinpocetine: A putative cerebral activator
Authors: Keim Kevin L. , Hall Pauliana C. 
Published: January 2005

AbstractResults from a series of standardized tests in rodents were used to describe the general neuropharmacology of vinpocetine, a putative cerebral activator. Vinpocetine was tested at doses ranging from 5 to 100 mg/kg p.o.; these doses are greater that its behaviorally active doses (i.e., 1 to 5 mg/kg p.o.). Vinpocetine did not impair rotarod performance or produce ataxia in mice. Vinpocetine antagonized electroconvulsive shock (ECS)‐induced convulsion in rats (ED50 = 28 mg/kg p.o.); however, neither ECS‐ nor pentylenetetrazol (PTZ)‐induced convulsions in mice were prevented by vinpocetine. The compound did not attenuate aggressive behavior in isolated mice. Vinpocetine decreased spontaneous loco‐motor activity (SLA) without affecting the rectal temperature in rats at doses greater than 25 mg/kg p.o., but the decrease was not dose‐related. Neither 10 nor 50 mg/kg p.o. of vinpocetine antagonized amphetamine‐induced stereotypy and exophthalmos in rats. In mice, vinpocetine (up to 100 mg/kg p.o.) did not antagonize reserpine‐induced catalepsy and ptosis or protect against tremorine‐induced lacrimation, tremor, salivation, or hypothermia. The lack of effect in these tests demonstrates that vinpocetine has little, if any, propensity to produce central nervous system (CNS) side effects.
Human safety profile of tolrestat: An aldose reductase inhibitor
Authors: Ryder Steven , Sarokhan Brenda , Shand David G. , Mullane John F. 
Published: January 2005

AbstractThe safety of tolrestat use in the diabetic patient was demonstrated by data from 14 double‐blind and open‐label studies conducted in 1,300 patients with diabetic neuropathy; the results were supported by data from earlier bioavailability, pharmacokinetic, and clinical pharmacology trials. There was a generally comparable frequency of complaints in the tolrestat dose groups and placebo groups. In a year‐long double‐blind study, the only complaint considered to by “possibly” drug‐related that occurred with a significantly greater incidence in patients treated with tolrestat than in those on placebo was dizziness. Laboratory test values recorded during the trials supported the positive safety findings of tolrestat. A review of blood urea nitrogen and serum creatinine values did not suggest any potential for tolrestat‐induced renal dysfunction. Infrequently, significant elevations in serum hepatic enzyme (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels occurred, accounting for 27 of 42 possibly drug‐related patient withdrawals following tolrestat administration. On review of these cases, it was concluded that tolrestat may cause hepatocellular damage with coincident elevations in AST and ALT in approximately 2% of patients. Importantly, the abnormalities were reversible after discontinuing the drug, commonly within 8–16 weeks. There was no evidence of a hypersensitivity syndrome in any patient in any study. These results support a favorable safety profile for tolrestat.
Investigations of the cardiac actions of SK&F 86466 in the rabbit
Authors: Macia Richard A. , Molyvdas Paschalio‐Adam , Poyatzi Afroditi , Sperelakis Nicholas , Matthews William D. 
Published: January 2005

AbstractThe cardiac effects of SK&F 86466, an α2‐adrenoceptor antagonist currently under evaluation in humans as an antihypertensive agent, were investigated in rabbits. In the isolated working rabbit heart, SK&F 86466 had no effect on spontaneous heart rate, contractility, coronary flow, aortic flow, or left ventricular pressure at concentrations from 10−7 to 3 × 10−5 M. At higher concentrations, SK&F 86466 lowered heart rate, contractility, aortic flow, and left ventricular pressure to such an extent that the heart failed to perform work. Electrophysiologic studies of spontaneous actions potentials of sino‐atrial node cells revealed that from 10−9 to 10−5 M, SK&F 86466 had no effect on action potential generation. At 3X 10−5 M, a 25% decrease in the rate of spontaneous action potentials was observed. This effect was accompained by a 1.3 V/sec decrease in + Vmax and a 25% increase in APD50. These results suggest that: 1) SK&F 86466 has no direct cardiodepressant action in rabbits at pharmacologically relevent doses, and 2) the actions of SK&F 86466 on the heart are most likely due to an effect on inward calcium current.
Pharmacological characterization of CGS 17867A as a benzodiazepine receptor agonist devoid of limiting behavioral effects
Authors: Bennett Debra A. , Amrick Caryl L. , Wilson Douglas E. , Boast Carl A. , Loo Patricia , Bernard Patrick S. , Schmutz Markus , Gerhardt Susan C. , Braunwalder Albert , Klebs Klaus , Yokoyama Naokata , Liebman Jeffrey M. 
Published: January 2005

AbstractCGS 17867A (2‐(4‐chlorophenyl)‐2,5,6,7,8,9,‐hexahydor‐3H‐pyrazolo [4,3,‐c]quinoline‐3‐one‐hydrochloride salt) is a tetrahydorpyrazoloquinoline related to the benzodiazepine (BZ) receptor agonist, CGS 9896. The compound is an effective inhibitor of [3H]flunitrazepam binding to the central BZ receptor (IC50 = 1.0 nM). Activity at the GABA‐A receptor and chloride channel components of the BZ receptor complex indicate a profile predictive of a partial agonist. CGS 17867A is orally active, block PTZ discriminative stimuli, produces an increase in conflict responding, and generalizes to CGS 9896 discriminative stimuli, indicating potential anxiolytic efficacy comparable to that of diazepam. This compound is more potent than diazepam in protecting rats against pentylenetetrazol‐induced convulsions and is effective in delaying the development of kindled seizures. Only moderate protection is noted against picrotoxin‐induced convulsions and no effect is produced by CGS 17867A against maximal electroshock‐ or strychnine‐induced convulsions. An absence of muscle relaxant properties is suggested by the inability of CGS 17867A to impair rotorod performance or to generalize to diazepam discriminative stimuli. Unlike CGS 9896, CGS 17867A does not antagonize diazepam‐induced rotorod deficit or diazepam discriminative stimuli. CGS 17867A potentiates ethanol‐induced rotorod impairment only at doses
in excess of those producing therapeutic efficacy, in contrast to the BZs, which induce both effects at comparable doses. Mice treated chronically with CGS 17867A do not show any tolerance or withdrawal effects upon subsequent testing. CGS 17867A produces a preclinical profile indicative of a partial BZ receptor agonist. The compound has anxiolytic and anticonvulsant potential and a reduced propensity to produce the limiting effects of the classical BZs.
Specificity of the effects of neuroleptics on the release of glutamate from the rat amygdala
Authors: Mott J. , Sherman A. D. 
Published: January 2005

AbstractThe purpose of this study was to determine if the depression of calcium‐dependent glutamate release from synaptosomes derived from the rat amygdala is specific to neuroleptics. To this end the effects of nine nonneuroleptic agents and nine previously untested neuroleptic agents (or isomers) on nondependent and calcium‐dependent glutamate release were determined by gas‐chromatographic and radioisotopic methods. All of the neuroleptics except reserpine depressed calcium‐dependent release at 10−7 M with only a weak, inconsistent reduction of nonspecific release. None of the nonneuroleptic agents at concentrations of 10−6 M 10−5 M produced depression of calcium‐dependent release without also strongly depressing nonspecific release. Reserpine was without effect on release at concentrations as high as 10−7 M. Also shown was that the representive neuroleptics Haloperidol, chlorpromazine, and clozapine depressed the calcium‐dependent release of glutamine‐derived glutamate to a greater extent over glucose derived glutamate. These data suggest that the specific depression of stimulus‐coupled glutamate release is not a characteristic of noneuroleptic compounds, but is highly associated with neuroleptics of the phenothiazine or butyrophenone classes.
Differential up‐regulation of D‐1 and D‐2 dopamine receptor function in mesostriatal areas but not in cortical‐limbic brain regions of rats chronically treated with (—)sulpiride and SCH 23390
Authors: Memo Maurizio , Pizzi Marina , Nisoli Enzo , Missale Cristina , Carruba Michele O. , Spano Pierfranco 
Published: January 2005

AbstractIn the present study, the possible functional modifications of both D‐1 and D‐2 dopamine (DA) receptor subtypes have been studied following chronic treatment with DA antagonists that selectively act on a single class of DA receptors. Particularly, the functional state of D‐1 and D‐2 receptors has been evaluated by measuring SKF 82526‐stimulated and bromocriptine‐inhibited adenylate cyclase activity in different brain regions of rats treated with saline, SCH 23390, or (−)sulpiride for 35 days.The results indicate that in striatum, nucleus accumbens, and substantia nigra, chronic blockade of D‐1 DA receptors by SCH 23390 induces up‐regulation of D‐1 receptors without changing the functional activity of D‐2 receptors. Likewise, chronic blockade of D‐2 DA receptors by (−)sulpiride causes an up‐regulation of D‐2 but not D‐1 DA receptors in striatum, nucleus accumbens, and substantia nigra. SCH 23390 or (−)sulpiride did not modify the functional activity of either D‐1 or D‐2 DA receptors located in frontal cortex and hippocampus. In conclusion, these results indicate that treatment with selective D‐1 or D‐2 DA receptor blockade for 5 weeks induces a receptor‐specific up‐regulation which involves the DA receptors located in the nigrostriatal system but not those present in the limbic‐cortical areas.
SL 81.0385: A novel selective and potent serotonin uptake inhibitor
Authors: Scatton Bernard , Claustre Yves , Graham David , Dennis Trevor , Serrano André , Arbilla Sonia , Pimoule Carmen , Schoemaker Hans , Bigg Denis , Langer Salomon Z. 
Published: January 2005

AbstractSL 81.0385 (4‐[(2‐naphthalenyl)methoxy]piperidine) is a potent competitive inhibitor of serotonin uptake into rat hypothalamic synaptosomes and human platelets (IC50 values of 18 and 13 nM, respectively), which exhibits a high selectivity for inhibiting serotonin uptake relative to noradrenaline or dopamine uptake in vitro. SL 81.0385 also exhibits potent serotonin uptake inhibiting properties in vivo as demonstrated by its ability to antagonize the p‐chloroamphetamine‐induced depletion of rat cerebral serotonin levels (ED50 = 2.5 mg/kg i.p.). Similarly, SL 81.0385 is a potent inhibitor of 3H‐imipramine and 3H‐paroxetine binding to the serotonin transporter complex in rat cortical membranes (Ki values of 0.5 and 3.2 nM, respectively), but it exhibits a much lesser affinity for radioligand binding to the noradrenaline, adrenaline, and dopamine transporters. The selectivity of SL 81.0385 for serotonergic systems is also demonstrated by its effects on cerebral monoamine metabolism. Indeed, SL 81.0385 decreases, ex vivo, endogenous 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the rat striatum, and, in vivo, extracellular 5‐HIAA concentrations (as measured by differential pulse voltammetry) in the rat cerebral cortex. In contrast, SL 81.0385 fails to decrease striatal levels of 3,4‐dihydroxyphenylacetic acid and homovanillic acid and hypothalamic levels of total, 3,4‐dihydroxyphenylethyleneglycol. SL 81.0385 is devoid of inhibitory activity toward monoamine oxidase and has no affinity for cerebral muscarinic, H1 histaminergic, α1‐, α2‐, and β‐adrenergic, D2 dopaminergic, and benzodiazepine receptors, and it possesses only weak affinity for 5‐HT2 receptors. The present results indicate that SL 81.0385 is a highly potent and selective inhibitor of serotonin uptake, chemically unrelated to the tricyclics, and it should find application in the treatment of depression, obesity, and alcoholism.
Atrial natriuretic factor: Structural requirements of the peptide for receptor binding, biological activity, and cGMP stimulation
Authors: Holleman William H. , Bush Eugene N. , Devine Edward M. , Firestone Susan L. , Rockway Todd W. , Sarin Virender K. , Budzik Gerald P. 
Published: January 2005

AbstractThe atrial natriuretic factor (ANF) family of peptides possesses diverse functional properties including smooth‐muscle relaxation, inhibition of aldosterone biosynthesis, and hypotensive activities. These separate activities are most likely mediated by the binding of the peptide to specific receptors located in the target organs. The present study was initiated to more closely examine the relationship between biological activity and the requirements of the various receptors for interaction with ANF and with ANF analogs. Binding affinities (Ki) were measured in plasma membranes isolated from rabbit kidney cortex, aorta, and adrenal, and in cultured rabbit aortic vascular smooth muscle cells (VSMC) using 125I‐Tyr‐28‐ANF (1–28) as the ligand. The VSMC were also utilized to quantitate stimulation of cGMP synthesis. Vasorelaxation (pD2) was measured in histamine‐contracted rabbit aortic rings. The activities of 19 ANF (5–28) analogs were compared, and a significant correlation between pD2 and Ki (r = −.83; p < 0.01) was obtained. The (D)Phe‐8 and Asn‐13 analogs were exceptions to this correlation; pD2 = 7.1 and 7.2, and pKi = 6.0 and 8.1, respectively. All analogs examined possessed comparable affinities in the four receptor assays. Conversely, comparison of vasorelaxant and cGMP stimulatory activities resulted in a much larger separation of activities. Tyr‐8 ANF (5–27) did not stimulate cGMP synthesis but relaxed smooth muscle (pD2 = 7.9), while ANF (7–23) was 500‐fold less active than ANF (5–28) in the vasorelaxant assay (pD2 = 6.1 and 8.9, respectively) but equipotent in the cGMP system. These and other experiments suggest the presence of ANF receptor subtypes and question the causative role of cGMP for inducing vasorelaxation of histamine‐constricted aortic rings.