bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparative analysis of various methods used to evaluate α‐adrenergic blocking activity of neuroleptic drugs
Authors: Kitzen Jan M. , Bixby Peter R. , Fielding Stuart 
Published: January 2005

AbstractEight neuroleptic drugs were studied for α‐adrenergic blocking activity using three different pharmacologic methods: (1) protection against norepinephrine lethality in rats (NEL), (2) inhibition of WB‐4101 binding in rat brain (WB), and (3) antagonism of pressor effects to norepinephrine in perfused rat hindquarters (DR10). Results from each of the methods were subjected to Spearman Rank correlation analysis in order to determine if NEL and WB would accurately predict α‐adrenergic blocking activity in the cardiovascular system. Both the NEL and WB assays were found to correlate significantly with results from the rat perfusion experiments. These results support the concept that WB‐4101 and NEL screening methods are valid predictors of cardiovascular α‐adrenergic antagonist activity.
Effects of new antiinflammatory steroids derived from prednisolone on pituitary‐adrenal axis and lysosomal stabilization
Authors: Heiman Ann S. , Nathoo Zulfikarali M. , Lee Henry J. 
Published: January 2005

AbstractThe pituitary‐adrenal axis suppression and lysosomal membrane stabilization of methyl steroid‐21‐oates, synthesized by modifying the 17β‐ketol side chain of prednisolone, were investigated by measuring plasma corticosterone and by determining abilities of the drugs to decrease extrusion of three liver lysosomal marker enzymes (acid phosphatase, beta‐glucuronidase, and aryl sulfatase) during incubation in severely hypo‐osmotic buffer. Animals were injected with 10 mg/kg drug suspensions i.m. at 20 hr and 2.5 hr prior to sacrifice. The parent compound prednisolone significantly suppressed pituitary adrenal function indicated by decreased plasma corticosterone levels. In contrast, the derivatives did not alter plasma corticosterone levels. When compared to controls, prednisolone, methyl 20‐dihydroprednisolonate, 1‐dehydro‐11β‐hydroxyandrostenedione, and to a lesser extent methyl prednisolonate retained significant lysosomal stabilization capacities, indicative of antiinflammatory activity. These data suggest that the new ester derivatives of prednisolone retained beneficial antiinflammatory activity but were devoid of significant adverse effects upon the pituitary‐adrenal axis.
Studies on GABA and cardiovascular function using in vivo and in vitro technics
Authors: DeFeudis Francis V. 
Published: January 2005

AbstractRecent in vivo and in vitro studies regarding the involvement of GABAergic systems in cardiovascular function have been reviewed and analyzed. It seems evident, from studies conducted with various GABA agonists and GABA antagonists, that activation of central GABAergic systems reduces sympathetic outflow from the hindbrain area of mammals, thereby producing bradycardia and hypotension. As GABA agonists can relax cerebral arteries, blood‐borne GABA might also play a role in cerebrovascular regulation. Further research concerning the mechanisms involved in GABA agonist‐induced cardiovascular responses could lead to the development of agents that might be effective in treating certain cardiovascular disorders of man, such as hypertension, cerebral atherosclerosis, migraine, and stroke.
Pre‐ and postsynaptic α‐adrenergic receptor effects of trazodone in the anesthetized dog
Authors: Gomoll Allen W. , Parmenter Keith 
Published: January 2005

AbstractThe α‐adrenergic blocking properties of trazodone were assessed in spinal‐sectioned, vagotomized dogs. Both the inhibition by clonidine of the tachycardia produced by continuous cardiac accelerator nerve stimulation (presynaptic effect) and the vasopressor effects of clonidine (postsynaptic effect) were antagonized by trazodone and phentolamine in this model. The results indicate that although it is 12–18 times less potent on a weight basis, trazodone, like phentolamine, blocks presynaptic α‐adrenergic receptors on the cardiac nerves of anesthetized dogs. Trazodone, unlike imipramine, did not potentiate the positive inotropic responses elicited by exogenously administered norepinephrine. The latter observation supports the interpretation that trazodone altered positive chronotropic responses to cardiac accelerator nerve stimulation via presynaptic α‐receptor blockade rather than by either an interference with neuronal reuptake of norepinephrine or a heightening of ß‐adrenergic receptor sensitivity.
Differential binding of guanabenz and its metabolites to cerebral α2‐receptors: The basis for a radioligand assay specific for the drug
Authors: Fluck Eugene R. , Homon Carol A. , Knowles John A. , Ruelius Hans W. 
Published: January 2005

AbstractGuanabenz (E‐2,6‐dichlorobenzylideneaminoguanidine acetate, Wy‐8678) and its identified metabolites were tested for their ability to displace [3H]clonidine from the cerebral α2‐receptors of rat and dog. The Kj's for inhibition of [3H]clonidine binding to rat membranes were 1.97, 0.96, 14.0, and 108 nM for clonidine, guanabenz, p‐hydroxyguanabenz, and the Z‐isomer of guanabenz, respectively. The other metabolites at concentrations of 10,000 nM did not displace [3H]clonidine. Scatchard analysis indicated single populations of binding sites with KD' s of 2.37 and 2.39 nM and Bmax's of 5.39 and 5.12 pmol/g for rat and dog preparations, respectively. Hill analysis yielded coefficients approximating unity, indicating a lack of cooperativity in binding. The high affinity of guanabenz relative to that of its metabolites for the α2‐receptor provided the basis for the development of an assay capable of discriminating guanabenz from its weakly hypotensive (p‐hydroxyguanabenz and the Z‐isomer of guanabenz) and pharmacologically inactive (2–6, dichlorobenzyl alcohol,2,6‐dichlorobenzaldehyde, 2,6‐dichlorobenzaldehyde azine, 2,6‐dichlorobenzaldehyde semicarbizone, creatinine adduct of 2,6‐dichlorobenzaldehyde, and an isomer of the creatinine adduct) metabolites. Antihypertensive agents with different mechanisms of action such as indoramin, prazosin, debrisoquine, and bethanidine bound little, if at all, and thus will not interfere with the assay of guanabenz.
The anorectic properties of opiate antagonists
Authors: Sanger D. J. , McCarthy P. S. , Lord J. A. H. , Smith C. F. C. 
Published: January 2005

AbstractThe effects of six opiate antagonists (naloxone, naltrexone, diprenorphine, Mr 1452, Mr 2266, and WIN 44,441) were studied on the food intake of food‐deprived rats. The potencies of these agents in standard tests of opiate antagonism were also measured. With the exception of WIN 44,441, all opiate antagonists reduced food consumption. However, all the active drugs had similar potencies in producing this effect whereas they had very different potencies in antagonizing the effects of opiates in vivo and in vitro. Furthermore, the anorectic action of the opiate antagonists differed in several respects from the effects produced by fenfluramine and diethylpropion. These results are consistent with a role for endogenous opioids in the control of appetite but suggest that the mechanisms involved may differ from those concerned in other opioid functions and from those mediating the actions of other anorectic drugs.
An alternative approach to developing dopamine‐receptor agonists with central presynaptic actions following oral administration: A comparison between apomorphine, bromocriptine, and the novel compound RDS‐127 (2‐di‐n‐propylamino‐4,7‐dimethoxyindane)
Authors: Arnerić Stephen P. , Long John P. 
Published: January 2005

AbstractRDS‐127 (2‐di‐n‐propylamino‐4,7‐dimethoxyindane) is a novel dopamine (DA) receptor agonist with potent central actions. RDS‐127, apomorphine (APO), and bromocriptine (BRM) were compared for their ability to inhibit locomotor activity in rats following oral administration. APO, BRM, and RDS‐127 produced time‐ and dose‐dependent decreases in locomotor activity. While APO and BRM were equipotent in inhibiting locomotor activity, RDS‐127 was 13.5 times more potent than either APO or BRM. A single oral dose of 32.0 μmol/kg of RDS‐127 decreased locomotor activity greater than 50% for a period of 2 hr. The inhibitory effects of RDS‐127 on locomotor activity were blocked by prior administration of sulpiride, suggesting the effects are mediated by DA receptors. While oral administration of APO or RDS‐127 generally decreased locomotor activity, similar doses given subcutaneously increased locomotor activity.These data suggest that the route of administration can profoundly affect the biological actions of DA receptor agonists and the accompanying conclusions concerning the selectivity with which they interact with different receptor subtypes. The therapeutic application and design of orally effective DA autoreceptor agonists are discussed.
The preclinical antipsychotic evaluation of HRP 913, a novel benzisoxazole derivative
Authors: Fielding Stuart , Novick William J. , Geyer Harry M. , Petko Wayne W. , Wilker Jeffrey C. , Davis Larry , Klein Joseph T. , Cornfeldt Michael 
Published: January 2005

AbstractHRP 913 {1‐[3‐(6‐fluoro‐1,2‐benzisoxazole‐3‐yl)propyl]‐4‐(2‐oxo‐1‐benzimidazolinyl)} piperidine demonstrated preclinical antipsychotic activity with features that may provide a clinical advantage over current therapy. It was effective in blocking amphetamine stereotypy in rats (ED50 = 0.4 mg/kg, i.p.), amphetamine circling in SN‐lesioned rats (ED50 = 0.3 mg/kg, i.p.), apomorphine stereotypy in rats (ED50 = 0.8 mg/kg, i.p.), but not apomorphine circling in SN‐lesioned rats (up to 10 mg/kg, i.p.). It also blocked Sidman avoidance in rats (ED50 = 0.17 mg/kg, i.p.) and monkeys (ED50 = 0.2 mg/kg, p.o.) and blocked intracranial self‐stimulation in rats (0.09 mg/kg, i.p.). A unique biphasic effect on catalepsy was found. Monkey EPS studies demonstrate a potential for EPS that is lower than some existing clinical standards. HRP 913 displaced 3H‐spiroperidol from rat striatal sites (IC50 = 6.0 × 10−9 M) and inhibited WB‐4101 binding (IC50 = 2.6 × 10−8 M) with only slight effect on QNB binding. HRP 913 does not appear to have marked α‐blocking properties in vivo. HRP 913 is a potent dopamine antagonist and is predicted to have less side effects than current therapy.
CGS 9896, a chloro‐derivative of the diazepam antagonist CGS 8216, exhibits anxiolytic activity in the pentylenetetrazol‐saline discrimination test
Authors: Spencer David G. , Lal Harbans 
Published: January 2005

AbstractThe effects of CGS 8216, a diazepam antagonist, and CGS 9896, a chloro‐derivative of CGS 8216, were assessed in an animal model of anxiety: discrimination of interoceptive discriminable stimuli (IDS) induced by pentylenetetrazol (PTZ). Rats were trained to discriminate the effects of an anxiogenic drug, PTZ, from those of saline by pressing one of two levers in an operant chamber. When given saline followed by PTZ (20 mg/kg), all subjects reliably selected the PTZ‐appropriate lever. When either diazepam or CGS 9896 (5, 20, or 80 mg/kg) injection preceded PTZ treatment, fewer subjects selected the PTZ‐appropriate lever. When given before either diazepam or CGS 9896, however, CGS 8216 (40 mg/kg) reversed their blockade of PTZ‐appropriate lever selection. These findings support the characterization of CGS 8216 as an effective diazepam antagonist, in vivo, with respect to an anxiolytic effect. CGS 9896 was effective in blocking the PTZ‐induced IDS, establishing anxiolytic action in this animal model of anxiety.
Picenadol, a mixed opioid agonist/antagonist without κ opioid agonist activity in the rat urination test
Authors: Leander J. David , Zimmerman Dennis M. 
Published: January 2005

AbstractPicenadol and its (+) and (−) isomers were compared to butorphanol and nalbuphine for their effects on urinary output in the normally hydrated rat. Butorphanol, a partial K agonist, increased urinary output markedly at all doses (0.32–20 mg/kg, s.c.). Nalbuphine (0.32–20 mg/kg, s.c.), picenadol (1.25–40 mg/kg, s.c.) and the two isomers (0.32–20 mg/kg, s.c.) had no tendency to increase urinary output within the 5‐hr test period. Nalbuphine did not affect bremazocine‐induced diuresis, whereas the (−) isomer of picenadol decreased bremazocine‐induced diuresis through a κ‐antagonist action and the (+) isomer of picenadol decreased the bremazocine‐induced diuresis through a μ‐opioid‐like agonist action. These results were interpreted to mean that nalbuphine is a mixed agonist/antagonist without activity at κ receptors. Picenadol is a mixed agonist/antagonist with potent μ‐opioid action in the (+) isomer and weak μ‐and κ‐antagonist action in the (−) isomer.
Chronic cardiovascular effects of bepridil in anesthetized and conscious dogs
Authors: Buckley Joseph P. , Steenberg Marie L. , Jandhyala Bhagavan S. 
Published: January 2005

AbstractThe chronic cardiovascular effects of bepridil were investigated in pentobarbital‐anesthetized dogs following chronic administration for 2 weeks and in awake instrumented dogs for 5 days. Prolonged administration of bepridil, 10 mg/kg, p.o., twice a day for 14 days produced a significant reduction in heart rate, cardiac output, and left ventricular minute work in dogs anesthetized approximately 12 hr following the last dose of the compound. Bepridil significantly increased coronary blood flow, whereas renal and mesenteric flows were not altered. Myocardial contractility was not significantly altered; however, left ventricular stroke work curves obtained during acute volume loading shifted to the left, indicating enhanced myocardial performance. Oral administration of bepridil twice daily produced a significant reduction in mean arterial blood pressure, a significant decrease in left ventricular stroke work and minute work, and myocardial oxygen consumption in awake animals. In addition, the compound decreased total peripheral resistance (TPR) in awake animals, whereas TPR was increased in anesthetized dogs.
Effects of alprazolam on the activity of rat cerebellar purkinje neurons: Evidence for mediation by norepinephrine
Authors: Sorensen Stephen , Freedman Robert 
Published: January 2005

AbstractAcute administration of alprazolam causes a dose‐dependent slowing of the spontaneous discharge of cerebellar Purkinje neurons. This effect is reversed by treatment with propranolol. There is also significantly less slowing in animals in which cerebellar neuronal circuitry has been destroyed by pretreatment with 6‐hydroxydopamine. These data suggest that some of the depressant effects of alprazolam may be mediated by an interaction with norepinephrine.
The neurotoxicity of homodimaprit (SKF‐91488): Sites of action assessed by the [14C]2‐deoxyglucose technique
Authors: Klein Michael C. , Poulakos Jennifer J. , Gertner Sheldon B. , Siegel Allan 
Published: January 2005

AbstractHomodimaprit (SKF‐91488) when injected into the lateral ventricle of the rat resulted in a delayed behavioral syndrome characterized by motor incoordination, hyperexcitability, and aggressive behavior, which occurred 18 hr after injection and ultimately caused death 24–72 hr after injection. In order to determine where the neural effects were occurring, the [14C]2‐deoxyglucose technique was utilized to identify possible sites of brain neural activation. Histological examination revealed that homodimaprit produced periventricular lesions at 18 hr. Autoradiographic analysis demonstrated increased ipsilateral activation in the nucleus accumbens, lateral septal nucleus, bed nucleus of the stria terminalis, caudato‐putamen, and the rostral half of the dorsal hippocampus. Bilateral activation was observed in the medial preoptico‐hypothalamus, midline thalamic nuclei including the mediodorsal nucleus, and the periventricular central gray. These findings suggest that the delayed behavioral effects of homodimaprit are probably the result of the activation of these specific areas of the brain and the resulting periventricular lesions. The mechanism by which homodimaprit produces these effects, however, remains unknown.
Preferential protection of cortical type II benzodiazepine receptors by γ‐aminobutyric acid during heat inactivation
Authors: Abel Marc S. , Lippa Arnold S. , Benson Donald I. , Beer Bernard , Meyerson Laurence R. 
Published: January 2005

AbstractPharmacological and biochemical evidence supports the existence of a heterogeneous population of benzodiazepine (BDZ) receptors. One major tool which has been used to identify distinct receptor subtypes is a novel series of triazolopyridazines (TPZ) that recognize two subpopulations (types I and II) of BDZ binding sites. Earlier studies demonstrated that γ‐aminobutyric acid (GABA) enhanced specific BDZ binding and protected a fraction of BDZ binding sites against heat inactivation. GABA/BDZ interactions were further investigated by studying the properties of those BDZ binding sites that are thermostable in the presence of 1.0 mM GABA when cortical membrane fragments are heated at 60°C. Saturation isotherms of 3H‐flunitrazepam (3H‐Flu) binding revealed a 90% and 60% diminution of binding sites in the absence and presence of 1 mM GABA, respectively. In the presence of 1 mM GABA, displacement of 3H‐Flu binding with varied concentrations of CL 218,872, a TPZ, in heated cortical membrane preparations indicated a significant increase in the IC50 value, with no effect on the Hill coefficient when compared to parallel control experiments with unheated membranes. In contrast, no significant differences in either Hill coefficients or IC50 values were obtained when similar displacement experiments were performed utilizing diazepam, an agent that does not distinguish between BDZ receptor subtypes. Hofstee plots of CL 218,872 displacement of 3H‐Flu binding were curvilinear in both heated and unheated membranes and could be resolved into two components by computer analysis. The relative affinity of CL 218,872 at the high‐affinity (KD1) or lowaffinity (KD2) recognition sites was unchanged after heating the membrane preparations. However, after heating, the density of type I receptors (Bmax1) was reduced 75%, while the number of type II receptors (Bmax2) was decreased only 38%. These results are indicative of a preferential GABA‐mediated protective effect on the thermal inactivation of type II BDZ recognition sites.
CGS 9896: A nonbenzodiazepine, nonsedating potential anxiolytic
Authors: Bennett Debra A. , Petrack Barbara 
Published: January 2005

AbstractVarious behavioral and neurochemical studies indicate that CGS 9896 may represent a novel, nonsedating anxiolytic. This substance, chemically related to the benzodiazepine antagonist CGS 8216, was effective in conflict and nonconflict models of anxiety. At the same time, CGS 9896 did not disrupt rotorod performance or decrease levels of responding in various operant procedures. In fact, CGS 9896 reversed the deficit in rotorod behavior produced by diazepam. CGS 9896 did not generalize to diazepam in rats trained to discriminate diazepam from vehicle. However, rats trained to discriminate CGS 9896 from vehicle generalized classical benzodiazepines to CGS 9896. These results suggest an anxioselective effect associated with CGS 9896 discriminative stimuli. Preliminary studies suggest that this pyrazoloquinoline does not produce dependence. Neurochemical analysis reveals that CGS 9896 binds avidly to benzodiazepine receptors both in vitro and in vivo. However, the binding characteristics of this compound differ from classical benzodiazepines in various respects. Two alternative hypotheses are discussed that may explain the behavioral and neurochemical differences between CGS 9896 and classical benzodiazepines.
Effects of some antiepileptic and proconvulsant drugs on kainic acid‐induced limbic epilepsy in cats
Authors: Cepeda Carlos , Martinez Adrián , Pacheco María Trinidad , Velasco Marcos 
Published: January 2005

AbstractThe effects of parenteral administration of diazepam (3 mg/kg), DL‐C‐allylglycine (60–80 mg/kg), and ketamine (20 mg/kg) on kainic acid (KA)‐induced limbic seizures were investigated in cats. Single microinjections of KA (1–4 μg) into the amygdaloid complex were followed by local sustained paroxysmal discharges in the limbic system. Seizures consisted of tonic clonic EEG discharges accompanied by orienting reaction to the ipsilateral side of injection and masticatory movements, facial jerks, and aggressive behaviour. Ictal discharges occurred every 5–10 min during the first hours after KA injection and then progressively disappeared within 1 wk. Interictal discharges remained for longer periods, but after 3 or 4 wk they were abolished. Diazepam completely blocked limbic seizures but not high‐frequency discharges in the site of injection and the ipsilateral hippocampus. The animals were protected for 30 to 60 min. At the same time, diazepam decreased multiple‐unit activity in the pontine reticular formation and the lateral geniculate nucleus and produced a general hypotonia state. DL‐C‐allylglycine activated KA amygdaloid focus during the remission state and ketamine produced independent epileptiformlike activity which interfered with that produced by KA injection.
Central GABA receptor stimulants as potential novel antihypertensive agents
Authors: Antonaccio Michael J. 
Published: January 2005

Abstractγ‐Aminobutyric acid (GABA) undoubtedly plays an important role as an inhibitory transmitter in the central nervous system. In recent years, evidence has accumulated which strongly suggests that GABA may specifically play a role in the central regulation of cardiovascular homeostasis. GABA apparently mediates a tonic hindbrain inhibition of vagal bradycardia, probably at nucleus ambiguus. In addition, evidence also suggests an additional GABA inhibitory input in the forebrain to sympathetic structures, possibly in the area of the periventricular hypothalamus. Thus, there appear to be at least two anatomically distinct and physiologically opposed GABAergic inhibitory mechanisms which function to control resting heart rate and reflex vagal activity. GABA also seems to be involved to some degree in the control of vasopressin release and respiratory function.Because of the physiological and pharmacological effects of centrally administered GABA or GABA mimetics, it is suggested that such agents might provide the basis for a new class of antihypertensive agents. Activation of central GABA receptors consistently reduces blood pressure and heart rate by a reduction in centrally mediated sympathetic nervous activity and, perhaps, a reduction in vasopressin release. Thus far, the GABA mimetics, THIP, imidazole‐4‐actic acid, muscimol, isoguvacine, isoarecaidine, kojic amine, as well as GABA itself, have all been shown to reduce blood pressure when centrally administered. Conversely, GABA antagonists, such as bicuculline and picrotoxin, raise blood pressure. Prodrugs of GABA or of other GABA mimetics can be used to allow for systemic administration of these agents with subsequent central penetration to provide an antihypertensive effect.Finally, it is suggested that the interaction of GABA with benzodiazepine receptors may allow for the development of new agents which, in addition to reducing stress‐induced cardiovascular responses, may prevent the development of hypertension.