bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serotonin uptake blockers inhibit the firing of presumed serotonergic dorsal raphe neurons in vitro
Authors: Rigdon Greg C. , Wang Ching M. 
Published: January 2005

AbstractSome antidepressant drugs are potent inhibitors of neuronal uptake of serotonin. In vivo, these compounds inhibit serotonergic dorsal raphe neuronal firing rates, presumably through increased stimulation of 5‐HT1a autoreceptors. We recorded from electrophysiologically identified serotonergic dorsal raphe neurons in rat brain slices and determined the effects of five serotonin uptake blockers on the firing rates of these units in vitro. Each drug decreased the neuronal firing rates in a concentration‐dependent manner. IC50 values derived from concentration‐response curves are: fluvoxamine, 0.8 μM; sertraline, 1.1 μM; imipramine, 2.7 μM; chlorimipramine, 2.8 μM; and fluoxetine, 4.2 μM. Exposure of brain slices to 10 μM tetrabenazine, a serotonin depleting agent, prior to treatment with serotonin uptake blockers resulted in a rightward shift of the concentration‐response curve. In vitro single unit recording allows: (1) direct comparison with neurochemical data obtained in vitro; (2) access to tissue bypassing blood brain barrier and liver enzymes; (3) quick wash out of drug from tissue; and (4) ability to record from single unitsover long periods (hours). This in vitro test provides a fast, simple means of determining neurophysiological effects of potential antidepressant drugs on the serotonin system.
Neurochemical and in vivo pharmacological profile of sertindole, a limbic‐selective neuroleptic compound
Authors: Sánchez Connie , Arnt Jørn , Dragsted Nils , Hyttel John , Lembøl Hanne Løve , Meier Eddi , Perregaard Jens , Skarsfeldt Torben 
Published: January 2005

AbstractSertindole (5‐chloro‐1‐(4‐fluorophenyl)‐3‐[1‐[2‐(2‐imidazolidinon‐1‐yl)ethyl]‐4‐Piperidyl]‐1H‐indole) is a new neuroleptic with a very high selectivity for dopamine (DA) neurones in the ventral tegmental area compared to DA neurones in substantis nigra pars compacta (Skarsfeldt, T., and Perregaard, J. Eur. J. Pharmacol. 182:613–614, 1990). Neurochemical and behavioural effects of sertindole have been investigated in comparison with the classical neuroleptics haloperidol and fluphenazine and the atypical neuroleptic clozapine. In vitro sertindole has high affinity for serotonin S2 (5‐HT2) receptors, DA D‐2 receptors, and α1‐adrenoceptors, moderate affinity for DA D‐1 receptors; low affinity for α2‐adrenoceptors, histamine H1 receptors and sigma receptors; and no affinity for 5‐HT1A, muscarine cholinergic receptors, and β‐adrenoceptors. The in vivo pharmacology is atypical, i.e., a remarkably weak or no effect in acute tests for DA antagonism, and the cataleptogenic potential is very low. Sertindole shows a very potent and long‐acting antagonism at central as well as peripheral 5‐HT2 receptors. The antagonistic effect at peripheral α1‐adrenoceptors is relatively weak in comparison with the 5‐HT2 antagonistic potency in vivo and in vitro. Sertindole shows no anticholinergic effects. In conclusion the pharmacological profile suggests that sertindole is an atypical neuroleptic compound with a low potential for extrapyramidal, autonomic, and anticholinergic side effects.
Antiarrhythmic effects of a novel Na+ and Ca++ channel blocker, SD‐3212: A comparison with its enantiomer (SD‐3211)
Authors: Miyawaki Nobuaki , Yamazaki Fumiko , Furuta Tatsuji , Shigei Tatsuro , Yamauchi Hideyasu 
Published: January 2005

AbstractThe electrophysiological and antiarrhythmic effects of a structurally novel compound, SD‐3212, were evaluated in comparison with its enantiomer (SD‐3211). In isolated guinea pig ventricular muscles, SD‐3212 reduced the maximum upstroke velocity and the plateau phase of action potential in a concentration‐dependent manner, while SD‐3211 significantly affected only action potential duration. SD‐3212 had oral prophylactic effects against both ouabain‐induced (in guinea pigs) and chloroform‐induced (in rats) arrhythmas, whereas SD‐3211 and verapamil were effective only on the former arrhythmia model and mexiletine was effective only on the latter. These results suggest that there is an enantiospecific interaction with cardiac Na+ and Ca++ channels, and that the dual inhibitory action of SD‐3212 on these channels may contribute to its antiarrhythmic properties.
Relationship between structure and efficacy at central benzodiazepine receptors for a series of imidazopyrimidines and imidazoquinolines
Authors: Gardner Colin R. , Budhram Paula , Deacon Robert M. J. , Thomson T. Andrew 
Published: January 2005

AbstractThe efficacy of a series of novel imidazoquinolines and imidazopyrimidines at benzodiazepine (BDZ) receptors was assessed using in vivo models: food‐motivated conflict in rats, stress‐induced ultrasounds in rat pups, leptazol seizures in mice, and suprahyoid muscle twitching in urethane‐anaesthetized rats. Compounds showing activities similar to classical BDZs (anxiolytic, anticonvulsant, and central nervous system (CNS) depressant activities, as well as depression of twitching) have been classified as strong agonists while those showing reduced CNS depressant effects, or reduced anticonvulsant effects with an antagonist profile in twitching, have been classified as moderate and weak partial agonists, respectively. Compounds were regarded as weak or strong inverse agonists according to their abilities to potentiate both seizures and twitching at doses which antagonize full BDZ agonists in the models of anxiety. Modification of two regions of these molecules caused changes in their efficacies. Agonist efficacy following modification to position 2 gave the ranking: oxadiazole > benzoyl > > cyclopropyl ketone ≧ thiazole with the latter compounds becoming inverse agonists in some cases, depending on other changes to the structure. The imidazoquinolines were stronger agonists than the imidazopyrimidines. As the 5,6‐substitutions on the imidazopyrimidines were reduced, compounds possessed less agonism and more inverse agonism, giving the agonism ranking 5‐methyl, 6‐allyl > 5‐methyl, 6‐ethyl > 5,6‐tetramethylene > 5‐ethyl,6‐H ≧ 5‐methyl,6‐H. Combination of the effects of modification of these two regions of the molecules has yielded a scheme which predicts the efficacy of individual members of the series. This scheme has been used to design other molecules with specific efficacies for BDZ receptors in this and other chemical series.
Bidirectional efficacy at benzodiazepine receptors of a series of imidazopyrimidines illustrated in drug discrimination studies
Authors: Gardner Colin R. , Budhram Paula 
Published: January 2005

AbstractMale Lister rats were trained to discriminate either chlordiazepoxide (CDZP), the benzodiazepine (BDZ) receptor partial agonist RU32698, or leptazol from vehicle on a fixed ratio 20 schedule. From 10 imidazopyrimidine BDZ receptor ligands tested four showed the profiles of agonists in that they substituted for CDZP and RU32698 and antagonized the leptazol cue. RU33203 depressed rates of responding in tests with all three cues, RU32698 only depressed responding at the highest dose in tests in the leptazol cue, and RU33543 or RU32514 did not alter rates of responding. Antagonism of the leptazol cue by RU32514 showed a 50% maximum. These data suggest that the agonist efficacies of these compounds rank RU33203>RU32698>RU33543>RU32514. The other six compounds showed inverse agonist profiles as they antagonized the CDZP cue and substituted for leptazol. Three compounds tested also antagonized the RU32698 cue. RU34113 was equipotent in antagonizing the CDZP cue and substituting for leptazol. RU33094 and RU34134 were clearly more potent in antagonizing the CDZP cue while RU33697, RU33356, and RU34000 showed intermediate profiles. All six compounds decreased rates of responding at doses that maximally antagonized the CDZP cue. These data suggest that RU34113 has the strongest inverse agonist efficacy and RU33094 and RU34134 the weakest efficacy. Structure‐efficacy relationships within this series of imidazopyrimidines are discussed.
Comparison of the stimulus effects of ethylketocyclazocine in fischer and Sprague‐Dawley rats
Authors: Locke Kenneth W. , Gorney Barbara , Cornfeldt Michael , Fielding Stuart 
Published: January 2005

AbstractThe discriminative stimulus effects of ethylketocyclazocine (EKC) were characterized in Fischer and Sprague‐Dawley rats trained to discriminate 0.3 mg/kg of EKC (s. c.) from saline in a two‐choice, discrete‐trial avoidance paradigm. The putative mu‐opioid receptor agonists morphine and fentanyl, as well as the putative kappa‐opioid receptor agonists EKC and U50,488H generalized completely with the EKC cue in both strains of rats. Only small quantitative differences between strains were observed in the generalization of these agonists with EKC. However, Sprague‐Dawley rats were notably more sensitive than Fischer rats to the depressant effects of fentanyl. Only small quantitative differences between strains were also observed in the dose of naloxone necessary for complete antagonism of the EKC‐like stimulus effects of the mu‐ and kappa‐opioid agonists. The mu‐opioid agonists were approximately 2–6 times more sensitive to naloxone antagonism than the kappa‐opioid agonists in both Fischer and Sprague‐Dawley rats. However, due to inter‐animal variability, this difference was not statistically significant. The results of this study suggest that one or more opioid receptor subtype(s) may be involved in the production of the EKC cue in both strains of rats.
Effect of p‐chloroamphetamine on morphine withdrawal syndrome
Authors: Lal Harbans , Reddy Chejerla 
Published: January 2005

AbstractAdult male rats were injected four times a day with increasing doses of morphine sulfate until a dose of 405 mg/kg/day was tolerated. After 5 days of maintenance at that dose, withdrawal signs were observed at 24, 48, and 72 hr of withdrawal. Given 4 or 18 hr after last morphine injection, a single administration (3–12 mg/kg) of p‐chloroamphetamine (PCA) blocked withdrawal “wet shakes” and ptosis during the following withdrawal period. Dose‐dependent reduction in withdrawal hypothermia was observed only at 24 hr of withdrawal. Writhing was blocked only at higher doses. Morphine‐withdrawal aggression measured at 72 hr of withdrawal and loss in body weight were not blocked by any delayed action of PCA. However, withdrawal aggression was blocked by PCA when given 1 hr before measurement at a dose of 3 mg/kg. Mice that were made morphine dependent by repeated injections of morphine given in large doses, exhibited withdrawal jumping either after cessation of morphine injections, or on injection of naloxone. PCA (3–12 mg/kg) given 2 hr before naloxone blocked this jumping in a dose‐dependent manner. It also blocked withdrawal jumping in morphine‐deprived mice when injected 2 hr, but not 14 or 17 hr before measurement. Jumping induced by α‐naphthyloxyacetic acid (α‐NOAA) was not blocked. The effect of PCA on different signs of morphine withdrawal is time dependent and may be related to its similarly time‐dependent effect on brain serotonin and dopamine.
Cholinergic agents: Deficits in rat hippocampal choline acetyltransferase activity and spatial working memory induced by intracerebroventricular administration of stoichiometrically prepared 1‐ethyl‐1‐(2‐hydroxyethyl) aziridinium ion (AF64A)
Authors: Moos Walter H. , Davis Robert E. , Kinsora Jack J. , Schwarz Roy D. , Smith Melvin E. , Spencer Carolyn J. 
Published: January 2005

AbstractA simplified procedure for preparing the cholinergic neurotoxin 1‐ethyl‐1‐(2‐hydroxyethyl) aziridinium ion (AF64A) is reported that employs stoichiometric base. When injected intracerebroventricularly into rats, stoichiometrically prepared AF64A causes impairments in spatial working memory in a water‐maze task. The behavioral changes are paralleled by deficits in hippocampal choline acetyltransferase activity, a neurochemical marker of the resulting cholinergic dysfunction.
Absence of anxiolytic effects of calcium channel antagonists
Authors: de Angelis L. 
Published: January 2005

AbstractThe potential anxiolytic effects of some calcium channel antagonists (nifedipine, nicardipine, and ±verapamil) were investigated in the elevated plus‐maze test in mice. The acute effects of the above‐mentioned drugs were compared with those of phenobarbitone and ±propanolol. Results showed that control mice spent less time in the open than in the closed arms, reflecting increased anxiety. Both phenobarbitone (20 mg/kg i.p.) and ±propanolol (5 mg/kg i.p.) increased the percentage of entries into open arms as well as the time spent on the open arms. Nifedipine (2 and 4 mg/kg i.p.), nicardipine (0.5 and 1.0 mg/kg i.p.), and ±verapamil (5 and 10 mg/kg i.p.) failed to alter significantly the behavior of mice. In summary, although there have been some reports based on other tests that calcium antagonists may have potential anxiolytic properties, this conclusion has not been supported by our results from the elevated plus‐maze test.
Cerebral metabolic effects of CI‐943 (8‐Ethyl‐7,8‐dihydro‐1,3,5‐trimethyl‐1Himidazo[1,2,‐c]pyrazolo[3,4‐e]‐pyrimidine), a potential antipsychotic drug
Authors: Kimes Alane S. , Raymon Lionel P. , Meltzer Leonard T. , Heffner Thomas , London Edythe D. 
Published: January 2005

AbstractCI‐943 is a novel drug candidate that has antipsychotic‐like activity in a variety of behavioral tests in rodents and primates, but has no affinity for brain dopamine (DA) receptors. In order to obtain information on the neuroanatomical substrates for its behavioral actions, we used the autoradiographic 2‐deoxy‐D‐[1‐14C]‐glucose method to map and quantify the distribution of CI‐943 effects on the regional cerebral metabolic rate(s) for glucose (rCMRglc) in the rat. The effects of CI‐943 (40 mg/kg) were assessed at 10 and at 60 min after the drug was administered intraperitoneally. In the globus pallidus and the substantia nigra pars reticulata, rCMRglc were increased at 60 min following treatment, and in the lateral habenula, rCMRglc was increased at 10 and 60 min after treatment. In contrast, the predominant effect of CI‐943 in other areas (e.g., most cortical, several thalamic, basal ganglia, limbic, and midbrain areas) was to reduce rCMRglc. The metabolic pattern produced by CI‐943 was unique and consistent with previous findings that CI‐943 resembles other antipsychotic drugs in behavioral tests but differs from those agents in tests prodictive of extrapyramidal dysfunction.
Comparison of the in vivo pharmacological profiles of sabeluzole and its enantiomers
Authors: Werbrouck Leen , Megens Anton A. H. P. , Stokbroekx Raymond A. , Niemegeers Carlos J. E. 
Published: January 2005

AbstractSabeluzole, a compound with pronounced cognitive enhancing, antihypoxic, and anticonvulsant properties, is the racemic mixture of the enantiomers R 84 439 (R‐configuration) and R 84 440 (S‐configuration). Sabeluzole and its separate enantiomers were compared in tests evaluating cognitive enhancing, antihypoxic, anticonvulsant, and secondary activity. Only small differences in potency were observed over species (mice, guinea pigs, and rats), routes of administration (i.p., s.c., and p.o.), and time intervals (ranging from 0.5 to 16 hr). R 84 440 was generally slightly more potent (up to 2.6 times) but also slightly shorter acting than R 84 439 (5 vs. 7 hr after s.c. administration in rats). The present data confirm and further extend the pharmacological profile of sabeluzole and indicate that both enantiomers contribute to its biological activity. Selection of one of the enantiomers instead of racemic sabeluzole provides no practical advantage in terms of potency, onset and duration of action, oral absorption, or therapeutic index.
Stereoselective antihypertensive effects of the calcium channel blocker RO 23‐6152 in two models of renin‐dependent hypertension
Authors: Dundore Ronald L. , Cox Bryan F. , Klevans Larry R. , Brody Michael J. 
Published: January 2005

AbstractTo compare antihypertensive effects, captopril, (+) diltiazem, the (+) and (−) enantiomers, and the racemic mixture of RO 23‐6152, 0.1–10 mg/kg, were administered intravenously to rats made hypertensive by occlusion of the abdominal aorta or by constriction of a renal artery. All drugs, with the exception of (−) RO 23‐6152, significantly decreased mean arterial pressure (MAP) and increased heart rate (HR). The (−) enantiomer of RO 23‐6152, 3 and 10 mg/kg, significantly increased MAP and decreased HR. Within the dosage range investigated (0.1–10 mg/kg), captopril, (+) diltiazem, and (+) RO 23‐6152 produced similar decreases in MAP. However, the racemate of RO 23‐6152 was significantly less effective in reducing MAP than (+) RO 23‐6152. We conclude that, with regard to antihypertensive activity, (+) RO 23‐6152 is as effective as captopril and (+) diltiazem. Furthermore, the antihypertensive effects of RO 23‐6152 are stereoselective.
Onset and recovery kinetics of V̇max reduction by class I antiarrhythmic agents: Relation to frequency dependence
Authors: Lee Martin Cynthia , Chinn Kevin 
Published: January 2005

AbstractThe onset and recovery kinetics of rate‐dependent n̈max reduction in guinea pig papillary muscles were measured for a new class I antiarrhythmic agent, bidisomide (SC‐40230), and compared to standard agents lidocaine, flecainide, and disopyramide. Frequency‐independent reduction of n̈max was found to be associated with long recovery time rather than onset kinetics or other factors, such as molecular weight. Bidisomide and flecainide had the slowest onset rates (τ=4 and 6 sec at 3.3 Hz, respectively) while lidocaine and disopyramide had much faster onset rates (τ=0.2 and 0.5 sec at 3.3 Hz, respectively). Recovery time constants were obtained by using the first n̈max value following a variable recovery time period after a stimulus train used to produce drug blockade. Flecainide and lidocaine had recovery time constants on the order of seconds (19 and 1 sec, respectively). Disopyramide, unlike previously reported, and bidisomide had very slow recovery time constants, on the order of minutes (2.4 and 8.8 min, respectively). The onset of n̈max reduction caused by bidisomide was most similar to flecainide, but the recovery time was most similar to disopyramide. The n̈max reduction caused by bidisomide and disopyramide was frequency‐independent (between 1 and 3.3 Hz), while that caused by flecainide and lidocaine was frequency‐dependent. Both bidisomide and disopyramide are frequency‐independent, which may be due to their long time constants for recovery from block.
Effects of HA‐966 on conflict, social interaction, and plus maze behaviors
Authors: Corbett Roy , Dunn Robert W. 
Published: January 2005

AbstractAntagonists at the N‐methyl‐D‐aspartate (NMDA) receptor share a number of properties, including anticonvulsant and anxiolytic‐like behaviors. In the Cook and Davidson conditioned conflict paradigm, the NMDA receptor complex antagonists HA‐966 (1 and 3 mg/kg), CPP (10 mg/kg), MK‐801 (0.03 mg/kg), and the benzodiazepine, diazepam (3 and 10 mg/kg) significantly disinhibited conflict responding. Likewise, in the social interaction test and elevated plus maze assay, two non‐conditioned paradigms predictive of anxiolytic activity, the NMDA antagonists HA‐966, CPP, and MK‐801, as well as diazepam, all significantly increased both social interaction time and open arm exploration time, respectively. In general, antagonism of the NMDA receptor complex results in anxiolytic behavior in rodents. Moreover, selective antagonism at the strychnine‐insensitive glycine modulatory site (HA‐966) may represent a new and novel class of compounds with potential therapeutic efficacy in anxiety.
Effects of buspirone and other anxiolytics on punished key‐pecking in the pigeon
Authors: Nanry Kevin P. , Howard James L. , Pollard Gerald T. 
Published: January 2005

AbstractPigeons were trained to peck a key on a multiple schedule of reinforcement in which 30 responses in the presence of a white cue light produced 3 sec of access to food, and 30 responses in the presence of a red cue light produced 3 sec of access to food and an electric shock, which suppressed responding. Intramuscular injection of the sedative‐hypnotic anxiolytics chlordiazepoxide (0.3–10 mg/kg), alprazolam (0.1–3.0 mg/kg), and zopiclone (10–100 mg/kg) substantially increased punished responding. The nonsedative anxiolytics buspirone (0.1–3.0 mg/kg) and ipsapirone (1.0 and 3.0 mg/kg) increased punished responding as much as did the sedative‐hypnotics. Buspirone had similar effects in benzodiazepine‐naive and benzodiazepine‐experienced pigeons. Chlorpromazine (tested at 1–30 mg/kg) and imipramine (tested at 1–30 mg/kg) only decreased unpunished responding at high doses. These results show that (1) the antipunishment effects of buspirone and ipsapirone in the pigeon are replicable in another laboratory, (2) buspirone's effect occurs in benzodiazepine‐experienced pigeons, and (3) alprazolam and zopiclone have antipunishment effects in the pigeon.
Electrocardiographic effects of zatosetron and ondansetron, two 5HT3 receptor antagonists, in anesthetized dogs
Authors: Williams Patricia D. , Cohen Marlene L. , Turk John A. 
Published: January 2005

AbstractThe pharmacology of 5‐hydroxytryptamine3 (5HT3)‐antagonists is an area under active investigation, and several agents of this class are currently under development for multiple therapeutic indications. Recently, two 5HT3 receptor antagonists of a tropane derived series, ICS 205 930 and zatosetron, have been shown to alter electrocardiographic properties of heart muscle. A prototypical, but structurally distinct (imidazole) 5HT3‐antagonist, ondansetron, was examined for its comparative cardiovascular activity in anesthetized dogs at intravenous doses of 0.66–5.25 mg/kg. Similar to zatosetron, a significant, dose‐dependent prolongation of the duration of the action potential of the electrocardiogram (Q‐Tc interval) occurred following ondansetron exposure, with a maximum increase of 28%. Other cardiovascular parameters (heart rate, mean arterial pressure, pulmonary pressure, cardiac output, peripheral vascular resistance, stroke volume and work index) were essentially unchanged by ondansetron treatment. At equivalent 5HT3 blocking doses, both ondansetron and zatosetron prolonged the Q‐Tc interval in anesthetized dogs similarly. However, for both compounds, the doses required to increase Q‐Tc interval were higher than the doses required to demonstrate 5HT3 receptor blockade. The fact that ondansetron, an imidazole, exhibited electrophysiological effects on cardiac muscle like the 5HT3 receptor antagonists derived from tropane suggests that the electrocardiographic effects are related to some property shared by 5HT3 receptor antagonists rather than a property of the tropane structure.
Centchroman: Binding with plasma proteins of rat, rabbit, guinea pig, and rhesus monkey
Authors: Ratna Sanjeev , Chandra Gyan , Ray Suprabhat , Roy S. K. 
Published: January 2005

AbstractIncubation of plasma samples rat, rabbit, guinea pig, and rhesus monkey showed a nonsaturable low affinity binding with 14C‐centchroman. The Scatchard analysis of binding data revealed a low affinity and high capacity binding of centchroman with plasma protein. It was observed that 14C‐centchroman did not compete with 3H‐cortisol, 3H‐estradiol, non‐steroidal estrogenic/antiestrogenic agents, or with the binding sites of other steroidal sex hormones used with plasma samples of different animals. The characterization of centchroman bound complex with polyacrylamide gel electrophoresis showed that centchroman binds with plasma albumin at af of 0.68.