bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of some antidepressants and flurazepam on an invertebrate model of 5HT neurotransmission
Authors: Gardner C. R.
Published: January 2005

5HT facilitates responses of field‐stimulated body wall of Lumbricus terrestris and induces rhythmic, spontaneous contractions. This response was also induced by the 5HT agonist 5‐methoxytryptamine, the 5HT releasers fenfluramine and p‐chloramphetamine, and the 5HT uptake blockers fluoxetine and chlorimipramine but not by catecholamines, octopamine, ACh, GABA, glutamate, histamine, adenosine, amphetamine, or amitriptyline.

5HTP was effective in the presence of a monoamine oxidase inhibitor. Fluoxetine potentiated 5HT and 5‐methoxytryptamine at concentrations that had little effect alone.

This response has been used as a model of 5HT transmission to study some psychotherapeutic drugs. Mepiprazole enhances 5HT transmission and may release 5HT. Trazodone also enhances 5HT transmission. Nomifensine inhibited body wall responses to field stimulation but induced no 5HT‐like activity. Viloxazine was inactive in this model. Flurazepam induced spontaneity but no increase in responses to field stimulation. This response is not similar to that of 5HT and may result from an action of flurazepam unrelated to 5HT mechanisms.
Prolonged treatment with the GABA agonist THIP increases dopamine receptor binding more than it changes dopaminergic behaviour in mice
Authors: Christensen A. V. , Hyttel J.
Published: January 2005

To investigate the influence of the GABA‐agonist, THIP, (4,5,6,7‐tetrahydroisoxazolo [5,4‐c] pyridin‐3‐ol) on the striatal dopaminergic system in mice after repeated administration, THIP, cis(Z)‐flupentixol, or haloperidol were given alone or in combinations for 12 days. The binding of 3H‐spiroperidol was greatly increased, and that of 3H‐cis(Z)‐flupentixol was slightly increased after treatment with THIP alone. After repeated treatment with neuroleptics, only slight increases in the binding were seen. There was no additive effect when treatments with THIP and the neuroleptics were combined.

Repeated administration of THIP did not induce changes in the ability of an acute dose of either haloperidol or cis(Z)‐flupentixol to antagonize methylphenidate‐induced stereotyped gnawing. The behavioural supersensitivity induced by chronic treatment with the two neuroleptics was not changed by concomitant treatment with THIP.
The discovery of psychotropic drugs by computer‐analyzed cerebral bioelectrical potentials (CEEG)
Authors: Itil Turan M.
Published: January 2005

The psychotropic properties of nine compounds were discovered in healthy subjects based on the effects of computer‐analyzed cerebral bioelectrical potentials or computer‐analyzed electroencephalograms (CEEG). Quantitative pharmaco‐EEG (QPEEG) studies demonstrated that CEEG profiles of mianserin (GB‐94), GC‐46, cyclacozine, mesterolone, and estradiol valerate, resembled the CEEG profiles of tricyclic antidepressants. CEEG profiles of d‐ and I‐norgestrel and cyproterone acetate showed similarities to benzodiazepine anxiolytics, and profiles of lisuride hydrogen maleate resembled psychostimulant compounds. Thus, antidepressant, anxiolytic, and “psychostimulant” effects were predicted for these compounds. Subsequent clinical trials confirmed the antidepressant effects of mianserin, GC‐46, and mesterolone in depressed patients; the anxiolytic effects of I‐norgestrel and cyproterone acetate in anxiety syndromes; and the “psychostimulant” properties of lisuride hydrogen maleate in the “geriatric” population. However, animal pharmacology and biochemical investigations failed to predict any psychotropic properties for these compounds.
Three‐dimensional computer modeling as an aid to drug design
Authors: Humblet Christine , Marshall Garland R.
Published: January 2005

Three‐dimensional computer graphic systems are an emerging tool in the design of therapeutic compounds. The molecular recognition process involved in drug‐receptor interaction implies a three‐dimensional stereospecificity shared by a set of drugs of similar pharmacological action. In investigating the pharmacophore, it is therefore necessary to go beyond two‐dimensional structures by including the description of the spatial properties of drugs.

This review describes both current and potential tools that a graphic computer can support to help the medicinal chemist in his structure‐activity puzzle. An outline of the systems presently in use for this purpose and a summary of recent applications is given. Some current developments undertaken in our research group are presented in the field of opiates, GABA, clonidine, antipsychotics, and S‐adenosyl‐L‐methionine inhibitors.
Bradykinin receptors in isolated intestinal smooth muscle
Authors: Chase Arleen , Volicer Ladislav
Published: January 2005

Although bradykinin has been long studied, its biological relevance is still unclear. The enzymes that form and degrade bradykinin appear to be numerous and ubiquitous, and its “receptors” are both species and tissue specific. Therefore, despite the fact that a multitude of compounds have been synthesized and screened as receptor antagonists, to date only one specific antagonist has been identified and it is only active in the rabbit aorta. This review is designed to present what is known about bradykinin receptors in intestinal smooth muscle. Relevant background material and a discussion of evidence for bradykinin's mechanism of action are also presented.
Reassessment of the anticonvulsant activity of diphenylacetylurea
Authors: Amato Robert J. , Jones Gary L.
Published: January 2005

On the basis of current information about the structure‐activity relationships of anticonvulsant compounds, it is predicted that diphenylacetylurea should possess some degree of antielectroshock activity. However, past attempts to demonstrate this have failed. In the present investigation the authors have determined that this compound does in fact possess such efficacy, although its potency is relatively low in comparison with phenytoin and phenobarbital. The difference in potency among these drugs is greatest when expressed in terms of the i.p. dosage, and much smaller when expressed in terms of blood or brain concentrations. The difference on the basis of i.p. dosage might be due to differences in bioavailability, but the lower potency of diphenylacetylurea expressed in terms of brain concentration is possibly due to its very high lipid solubility, as discussed in the text.
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

Eight 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

The 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

Recent 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

The 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

Guanabenz (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

The 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

RDS‐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

HRP 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

The 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

Picenadol 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

The 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

Acute 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

Homodimaprit (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

Pharmacological 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

Various 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

The 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

γ‐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.
The behavioral pharmacology of Ay‐27,110, a novel nonergot dopaminergic agonist
Authors: Voith Katherine
Published: January 2005

AY‐27,110 is the pharmacologically active enantiomer of a troponylpiperazine derivative. At low doses, the compound induced contralateral rotational behavior in rats with a unilateral 6‐OHDA lesion of the nigrostriatal pathway, at higher doses it caused weak stereotypy and in dogs in elicited emesis. The actions of AY‐27,110 were dose‐dependently antagonized by haloperidol and pimozide, but were not diminished by α‐MPT or reserpine pretreatment. These results indicate that AY‐27,110 is a chemically novel dopaminergic agonist that should be useful as an anti‐parkinson drug. Since the effects of AY‐27,110 are independent of intact catecholamine synthesis and storage mechanisms, the compound should be efficacious in patients with advanced Parkinson's disease. AY‐27,110 was compared to several ergot‐derived dopamine agonists, namely bromocriptine, lisuride, and pergolide, in order to predict its potency, side‐effect liability, and potential therapeutic advantages.
Further studies on the distinctive sleep‐wakefulness profiles of antihistamines (astemizole, ketotifen, terfenadine) in dogs
Authors: Wauquier A. , van Den Broeck W. A. E. , Awouters F. , Janssen P. A. J.
Published: January 2005

The effects of the antihistamines astemizole, ketotifen, and terfenadine, given orally at the dose of 10 mg/kg, were investigated on 16‐hr sleep‐wakefulness patterns in dogs. As determined in the Ascaris allergy test in dogs, this dose had marked antihistaminic activity for at least the total duration of the recording. Using a computerized on‐line analysis and automatic sleep classification, a differentiation was made between wakefulness, transition to sleep, slow‐wave sleep, and REM (or paradoxical) sleep. Astemizole did not significantly change sleep‐wakefulness patterns. Ketotifen significantly increased slow‐wave sleep and significantly decreased REM sleep. Terfenadine significantly decreased wakefulness and significantly increased both slow‐wave sleep and REM sleep. With both ketotifen and terfenadine, REM latency was prolonged. Two different mechanisms appear to be involved in the REM sleep effects seen with terfenadine: an early REM sleep suppressant effect and a late but large REM sleep‐enhancing effect. This study shows central effects of terfenadine that are not completely typical for H1 antagonists but which are very pronounced at a dose producing much weaker peripheral antihistamine activity than the same dose of ketotifen and astemizole.
Neuropathological processes in Alzheimer's disease
Authors: Price Donald L. , Struble Robert G. , Whitehouse Peter J. , Kitt Cheryl A. , Cork Linda C.
Published: January 2005

During the past few years, substantial progress has been made in understanding the neuropathology of Alzheimer's disease (AD) and its late‐life variant, senile dementia of the Alzheimer's type. Neurofibrillary tangles have been shown to be composed of cross‐linked, highly insoluble paired helical filaments. The disease selectively affects certain populations of nerve cells, including those in the amygdala, hippocampus, neocortex, locus coeruleus and basal forebrain cholinergic (Ch) system. Changes in the latter system account, in substantial part, for the decrease in cortical Ch markers which, to date, appear to be the earliest and most consistent abnormalities in the brains of individuals with AD. Neuritic plaques have been shown to be foci of axonal/synaptic pathology consistent with the concept that these changes may be associated with a chronic distal axonopathy involving certain populations of nerve cells. Recent studies in aged nonhuman primates suggest that some of the abnormal axons/terminals in neuritic plaques may be derived from the basal forebrain Ch system. Understanding the biological mechanisms leading to these structural changes is essential if we are to understand the pathogenesis of the clinical manifestations of AD and if we are to design rational therapeutic approaches to treat this disorder.
Is it possible to design rational treatments for the symptoms of Alzheimer's disease?
Authors: Davies Peter
Published: January 2005

This paper reviews and discusses the evidence that the primary cause of the symptoms of Alzheimer's disease is a deficiency of acetylcholine in cerebral cortex and hippocampus. Data on other neurotransmitters in this disease are briefly reviewed. Possible means of treating acetylcholine deficiences are discussed.
Development of cholinergic drugs for the treatment of Alzheimer's disease
Authors: Johns Celeste A. , Haroutunian Vahram , Greenwald Blaine S. , Mohs Richard C. , Davis Bonnie M. , Kanof Phil , Horvath Tom B. , Davis Kenneth L.
Published: January 2005

Alzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long‐term habituation of locomotor activity and retention of a one‐trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long‐term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy in AD.
Interaction of astemizole and other drugs with passive cutaneous anaphylactic and histamine‐, serotonin‐, and compound 48/80‐induced skin reactions in the rat: A Procedure to determine anti‐allergic effectiveness
Authors: Awouters Frans , Niemegeers Carlos J. E. , Janssen Paul A. J.
Published: January 2005

Passive cutaneous anaphylactic (PCA) reactions in rats were induced simultaneously with skin reactions to intradermally injected histamine, serotonin, and compound 48/80. In this test compounds with widely different pharmacological profiles were studied to evaluate the significance of anti‐allergic activity. Five cromoglycatelike drugs, injected i.v. 5 min before antigen challenge, were either devoid of activity or significant inhibition of PCA reactions was associated to inhibition of histamine and compound 48/80 reactions. Two histamine H1‐antagonists, astemizole and ketotifen; the serotonin S2‐antagonist ketanserin; and the α‐adrenergic blocking agent prazosin were tested over a wide dose range 2 hr after s.c. administration. Prazosin, as a result of systemic hemodynamic effects, significantly inhibited the four reactions (primarily PCA), but complete inhibition was not obtained. Ketanserin primarily inhibited serotonin reactions, and inhibition of other reactions required high doses. Ketotifen was a very potent and apparently competitive inhibitor of histamine reactions, with a significant effect on PCA and compound 48/80 reactions. Astemizole primarily inhibited histamine and PCA reactions; complete inhibition was reached for the four reaction types. In terms of a practical definition of anti‐allergic drugs, i.e., compounds capable of fully suppressing the consequences of allergen challenge in the absence of nonspecific systemic effects, astemizole appears to be a prototype.
Cardiovascular actions of an experimental antitumor agent, homoharringtonine, in anesthetized dogs
Authors: Lokhandwala Mustafa F. , Sabouni Majd H. , Jandhyala Bhagavan S.
Published: January 2005

Cardiovascular actions of homoharringtonine, a plant extract currently being tested for clinical efficacy as an antitumor agent, were investigated in anesthetized mongrel dogs. Intravenous administration of homoharringtonine (4 mg/M2) produced significant reductions in heart rate, cardiac output, and arterial blood pressure, while myocardial contractility or total peripheral resistance were not altered. These results suggest that the bradycardia could account for decreases in both cardiac output and blood pressure. In additional experiments performed to evaluate the actions of homoharringtonine on cardiac sympathetic neurotransmission it was discovered that this compound caused significant impairment of the tachycardia elicited during stimulation of cardiac sympathetic nerves. The positive chronotropic effects of either norepinephrine or isoproterenol were not altered by homoharringtonine. In these animals in which both vagi and the right cardioaccelerator nerve were sectioned, the hypotensive and bradycardiac effects were of lesser magnitude than that seen in neurally intact animals. These results show that a dose of homoharringtonine comparable to that used in clinical trials produces hypotension and bradycardia which may result from inhibition of sympathetic nerve function caused by the compound.
Effect of secoverine HCl on motor and myoelectrical activity of the sigmoid colon in man
Authors: Meshkinpour Hooshang , Hoehler Fred
Published: January 2005

Secoverine hydrochloride is a new synthetic tertiary amine with selective muscarine blocking effect. Its tendency to produce parasympathetic side effects has been claimed to be almost 100 times less than atropine. We studied the role of secoverine on meal‐induced colon motor and myoelectrical activity in 12 healthy volunteers. Intraluminal pressure changes, slow wave activity, and spike frequency of the sigmoid colon as well as a pneumogram, blood pressure, and electrocardiogram were monitored. Fifteen minutes after ingestion of a 1000‐kcal meal, subjects received 4 mg secoverine or the same volume of normal saline in separate sessions and recording continued for another 90 minutes. Ingestion of the meal increased colon motor and spike activities; however, these parameters were not influenced by secoverine. Drug treatment did not change the proportion of slow wave activity and did not affect pulse rate, blood pressure, respiration rate, or electrocardiogram in a significant fashion. In conclusion, intravenous injection of 4 mg secoverine had no effect on meal‐stimulated colon motor and myoelectrical activity. Whether this medication at a different dose regimen has therapeutic value remains to be seen. However, this dose of secoverine was well tolerated by the subjects.
AHR‐9377, a new antidepressant agent
Authors: Johnson David N. , Ruckart Robert T. , Turley Brenda G.
Published: January 2005

AHR‐9377 is a novel chemical structure with potential antidepressant activity. It was more potent than imipramine in mice, and equipotent with imipramine in rats in blocking tetrabenazine ptosis. Yohimbine toxicity in mice was potentiated by AHR‐9377 in doses less than those of imipramine. The compound had no CNS stimulant properties as judged by behavioral observations and spontaneous motor activity determinations in rats and by its lack of effect on rectal temperature of normothermic rats. In rats made hyperthermic with d‐amphetamine, however, AHR‐9377, like imipramine, prolonged the hyperthermic effect. Contractions of the cat nictitating membrane that were induced by norepinephrine were potentiated by AHR‐9377. Unlike iproniazid, AHR‐9377 had no monoamine oxidase‐inhibiting activity. Electroencephalographic analyses indicated no slowing of cortical activity and no spindle‐type waves in cats after AHR‐9377 administration. These data suggest that AHR‐9377 is a potential antidepressant agent without sedative activity.
Effect of treatment with some atypical antidepressants on 3H‐DHA binding in rat brain
Authors: Pandey Ghanshyam N. , Brown Barbara , Davis John M.
Published: January 2005

The mechanism of therapeutic action of antidepressant drugs has been related to their effects on metabolism and release and reuptake of catecholamines and serotonin. Some atypical antidepressants, however, do not have such pharmacological effects. Recently it has been reported that most of the antidepressant drugs cause down regulation of beta adrenergic receptors in rat brain after chronic treatment. In order to examine if this is a common and specific pharmacologic property of all antidepressant drugs, we have studied the effects of treatment with some atypical antidepressant drugs on beta adrenergic receptor binding in rat cortex using 3H‐dihydroalprenolol (DHA) as the radiolabeled ligand. Our results indicate that chronic treatment with almost all antidepressants studied causes down regulation of beta adrenergic receptors. However, such effects are not observed after treatment with neuroleptics such as haloperidol or chlorpromazine or psychomotor stimulants such as cocaine. This approach thus provides a useful method of screening potential antidepressant drugs.
Modification by diazoxide of canine renal vascular responsiveness to endogenous vasoconstrictors
Authors: Wood William B. , Sticht Frank D. , Igbokwe Emmanuel C. , Cardoso Sergio S. , Elko Edward E.
Published: January 2005

Diazoxide‐induced modification of renal vascular responses to norepinephrine and angiotensin II was studied in dogs. Diazoxide was infused directly into the renal artery in order to minimize the effect of high plasma protein binding and to obtain maximum exposure of the test vessel to the administered drug. During the 30‐min infusion period, renal blood flow showed an initial, transitory increase followed by a progressive decline which paralleled the induced fall in systemic blood pressure. In the presence of diazoxide, renal vasoconstrictor responses to intravenous and intraarterial norepinephrine and intravenous angiotensin II were significantly attenuated. In contrast, the renal vasoconstrictor response to intraarterial angiotensin II was not significantly modified by diazoxide. This differential inhibition by diazoxide of renal vasoconstriction to norepinephrine or angiotensin II may warrant consideration when these pressor agents are being used to overcome the excessive hypotension resulting from inadvertent diazoxide overdosage.
A pharmacological analysis of the rat mast cell 5‐HT gastric lesion test and the effects of ketanserin
Authors: Awouters Frans H. L. , Niemegeers Carlos J. E. , Janssen Paul A. J.
Published: January 2005

Pronounced lesions of the gastric mucosa were induced by Compound 48/80 (1.0 mg/kg, i.v.) in rats protected from lethal shock of released histamine by the experimental histamine H1‐antagonist R 37 617. The intensity score of the lesions correlated with serum pepsinogen levels. Generally the stomachs were greatly distended and contained blood and regurgitated food residues. Compounds from many different pharmacological classes were tested in this procedure. Complete protection was obtained with serotonin antagonists. Also isoproterenol and salbutamol fully protected, apparently by counteracting the serotonin‐induced circulatory stasis. No obvious effect was obtained with antagonists of acetylcholine, dopamine, and histamine, with α‐ and β‐adrenergic blocking agents, with narcotic analgesics, and with various other agents unless doses were administered that by far exceeded the range of their primary activity. The lowest ED50 of ketanserin for protection was 0.15 mg/kg (time—2 hr, both s.c. and p.o.), indicating its high oral effectiveness against venoconstriction induced by endogenous serotonin. These doses also abolished cyanosis and reduced stomach distension, abnormal gastric contents, and serum pepsinogen levels. In view of the recently elucidated differences between serotonin antagonists, the mast cell 5‐HT gastric lesion test appears appropriate to measure the peripheral serotonin S2‐antagonism of compounds.
The activity of nifedipine, diltiazem, verapamil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity
Authors: Kenakin Terry P. , Beek Deborah
Published: January 2005

A characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazem, verapamil, and lidoflazine. All drugs produced relaxation of K+ depolarized guinea pig ileal longitudinal muscle strips and K+ depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration‐response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA2 estimates: nifedipine 9.5, diltiazem 7.65, verapamil 7.8, and lidoflazine 7.0. Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine‐contracted rabbit aortae while weak effects were observed with verapamil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazem displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this regard.
Alprazolam: Review of pharmacological, pharmacokinetic, and clinical data
Authors: VonVoigtlander Philip F. , Straw Robert N.
Published: January 2005

Alprazolam is a recently marketed triazolobenzodiazepine. The animal pharmacological data reviewed here suggest a potent anxiolytic action. But, in addition, an antidepressant activity was revealed in clinical studies and subsequently studied in animal assays. As an extension of these activities, alprazolam also displays efficacy in panic and phobic disorders. Data relating to a wide range of pharmacological activities and pharmacokinetics of alprazolam are also reviewed.