The effects of tofisopam,a 3,4-benzodiazepine,in animal models of anziety,sedation, and convulsions

Tofisopam, a 3, 4-benzodiazepine classified as a nonsedative anxiolytic in man, had no effect in two animal tests of anxiety (the social interaction test and a punished drinking test; 10--50 mg/kg) and produced a dose-related reduction in exploratory and locomotor activity in the holeboard (5--100 mg/kg). These reductions were not antagonised by chlordiazepoxide (5 mg/kg), Ro 15--1788 (10--20 mg/kg), or picrotoxin (2 mg/kg); however, the reductions in head-dipping but not in motor activity or rears were antagonised by CGS 8216 (10 mg/kg). Tofisopam (10--50 mg/kg) had no anticonvulsant activity, but had proconvulsant activity, with picrotoxin and pentylenetetrazole. In contrast, tofisopam (50--100 mg/kg) antagonised the convulsions induced by the 1, 4-benzodiazepine Ro 5--4864.     

CGS 9896, a chloro-derivative of the diazepam antagonist CGS 8216, exhibits anxiolytic activity in the pentylenetetrazol-saline discrimination test

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.     

Anxiolytic action of CGS 9896 on mouse exploratory behavior

A new non-benzodiazepine compound proposed as a non-sedating anxiolytic was tested in the mouse exploratory model of anxiety. CGS 9896 significantly increased the number of light dark transitions at doses beginning at 7.5 mg/kg i.p. Analysis of general locomotor activity at these doses revealed no change in spontaneous motor activity in a photocell equipped activity monitor. Pretreatment with the benzodiazepine receptor antagonist, Ro15-1788, 10 mg/kg i.p., blocked the increase in light dark transitions produced by CGS 9896. These data support the interpretation that CGS 9896 acts as an anxiolytic through the benzodiazepine receptor, and appears to have no sedating properties within the anxiolytic dose range.     

In silico and in vivo investigation of ferrocene‐incorporated acyl ureas and homoleptic cadmium carboxylate derivatives for anticonvulsant,anxiolytic, and sedative potential

In this study different derivatives of ferrocene‐incorporated acyl ureas and homoleptic cadmium carboxylates were investigated for potential anticonvulsant, anxiolytic and sedative properties, using in‐silico and in‐vivo techniques. The molecular docking studies reveled that ferrocene compounds derivative 1‐(4‐bromobenzoyl)‐3‐(4‐ferrocenylphenyl) urea (PB1) and cadmium compounds derivative bis (diphenylacetato) cadmium (II) (DPAA) exhibit binding affinities against various neurotherapeutic molecular targets involved in epilepsy, anxiety, and sedation. Both PB1 and DPAA showed high binding affinities against protein targets like mammalian shaker voltage dependent potassium channel beta subunit complex, calcium release‐activated calcium channel, sodium channel 2A inactivation gate, human sodium/hydrogen exchanger regulatory factor, and gamma amino butyric acid A receptor associated protein. PB1 (2–10 mg/kg) and DPAA (1–5 mg/kg) delayed onset time of pentylenetetrazole‐induced myoclonic jerks and tonic‐clonic seizures in mice while decreased duration of tonic‐clonic seizures, determining the anticonvulsant effect of these compounds. PB1 and DPAA (0.5–1 mg/kg) exhibited anxiolytic effect by increasing time spent and number of animals entries into open arms, while decreasing time spent in dark compartment. Furthermore, PB1 (0.5–1 mg/kg) and DPAA (0.1–1 mg/kg) reduced onset time of sleep and increased duration time of sleep in mice, showing sedative effect. Taken together, our results indicate that aforementioned derivatives of ferrocene and cadmium are potent neurotherapeutic agents possessing anticonvulsant, anxiolytic and sedative properties.     

Evaluation of the Anticonvulsant and Anxiolytic Potentials of Methyl Jasmonate in Mice

Methyl jasmonate (MJ) is one of the most well-studied plant stress hormones belonging to the jasmonate family. Previous studies have shown that MJ potentiated pentobarbitone sleeping time and enhanced GABA-mediated inhibitory neurotransmission, suggesting potential benefits in disorders associated with hyperactivity of the brain. This study was carried out to evaluate whether MJ has anticonvulsant and anxiolytic properties in mice. The anticonvulsant effect was assessed based on the prevention of tonic-clonic seizures induced by chemoconvulsant agents in mice. The anxiolytic property was evaluated utilizing the elevated plus maze (EPM) and light/dark transition paradigms. The effect of MJ on spontaneous locomotor activity (SMA) was also assessed. Mice received intraperitoneal (i.p.) injections of MJ 30 min before the tests were carried out and diazepam (2 mg/kg, i.p.) was used as the reference drug. MJ (50–400 mg/kg) did not protect the mice against tonic-clonic convulsions induced by picrotoxin (10 mg/kg, i.p.) or strychnine (3 mg/kg, i.p.). However, MJ (100, 200, and 400 mg/kg) offered 20, 60, and 100% protection against pentylenetetrazole (100 mg/kg, i.p.)-induced convulsions. In a similar manner to diazepam (2 mg/kg), MJ (400 mg/kg) produced a marked sedative effect as shown by decreases in the number of lines crossed and the duration of ambulation in the open field test. In contrast to diazepam (2 mg/kg), MJ (5–50 mg/kg) did not show anxiolytic effects in the EPM and light/dark transition paradigms. These findings suggest that methyl jasmonate at high doses possessed anticonvulsant properties in the pentylenetetrazole animal model of epilepsy, but did not produce anxiolytic activity in mice.     

Lack of tolerance or withdrawal effects in mice after chronic administration of the non-sedating anxiolytic, CGS 9896

CGS 9896, a non-sedating anxiolytic, was compared to diazepam with respect to the development of tolerance and withdrawal. Both compounds were administered daily to mice at various doses (3, 10 or 30 mg/kg) for periods of up to 4 weeks. Measures of sedation/muscle relaxation, motor activity and anticonvulsant effects were then assessed. When administered acutely, CGS 9896 increased motor activity, had no effect on traction reflex, and elevated the threshold for PTZ-induced convulsions. After chronic administration of CGS 9896, no changes in these parameters were observed compared to the effects seen after acute treatment. Acute administration of diazepam reduced motor activity, impaired traction reflex and increased PTZ-induced convulsion threshold. Tolerance developed to the effects of diazepam in all three measures. Following a four week dosing period with 30 mg/kg of either CGS 9896 or diazepam, the drugs were withdrawn and similar behavioral measures obtained at various withdrawal intervals up to 15 days. In separate groups of mice, precipitated withdrawal was also assessed by the administration of the benzodiazepine agonist, CGS 8216. No effects were observed after any period of withdrawal from CGS 9896. By contrast, withdrawal from diazepam resulted in significant alterations of motor activity and convulsion threshold. These results indicate that CGS 9896 is likely to be free of undesirable tolerance and withdrawal effects typically associated with the benzodiazepines.     

Discriminative stimulus properties of CGS 9896: interactions within the GABA/benzodiazepine receptor complex

Male rats were trained to discriminate the stimulus effects of CGS 9896 (30.0 mg/kg) from its vehicle. Once trained, discriminative performance was observed to be dose-responsive in the 3.75-30.0 mg/kg range and analysis of the dose-response curve generated an ED50 of 6.44 mg/kg. Generalization testing with chlordiazepoxide and pentobarbital produced CGS 9896-appropriate responding, whereas administration of the GABA agonists SL 75 102 resulted in 75% (intermediate) generalization to the CGS 9896 discriminative stimulus. Although full antagonism of the CGS 9896 cue was obtained following administration of Ro15-1788 and pentylenetetrazole, the inverse agonist DMCM failed to provide complete antagonism. These results suggest that the discriminative properties of CGS 9896 are consistent with its activity as a benzodiazepine receptor agonist.     

Yohimbine-induced seizures in mice: A model predictive of potential anxiolytic and GABA-mimetic agents

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

Influence of etoricoxib on anticonvulsant activity of phenytoin and diazepam in experimental seizure models in mice

Objectives Our aim was to investigate the effect of etoricoxib on the anticonvulsant activity of phenytoin and diazepam against seizure models in mice. In addition the acute adverse effect of etoricoxib was assessed with a chimney test. Methods The maximal seizure pattern was induced in mice by giving an alternating current of 50 mA for 0.2 s, while chemical seizures were induced by intraperitoneal injection of pentylenetetrazole at its CD97 dose (97% convulsive dose for the clonic phase). Test drug was administered 45 min before the electrical or chemical induction of seizures in combination with conventional antiepileptics. The ability of the test drug to reduce or abolish the extensor phase of maximal electroshock and clonic‐type seizures in the chemical induction method was selected as anti‐seizure criteria. Key findings Concurrent treatment with etoricoxib at an oral dose of 10 mg/kg reduced the anticonvulsant potency of phenytoin. The protective effects of diazepam against pentylenetetrazole‐induced convulsions was significantly increased and the mortality rate was reduced by concurrent treatment with etoricoxib (10 mg/kg p.o.) when compared with diazepam groups. No neurotoxic effect was observed with etoricoxib (10 mg/kg p.o.) and it had no impact on motor coordination in the chimney test in mice. Etoricoxib applied at its highest dose (10 mg/kg) significantly enhanced the free plasma levels of diazepam whereas the free plasma levels of phenytoin were significantly reduced. Conclusions The obtained results suggest that the preferential cyclooxygenase‐2 inhibitor etoricoxib significantly reduced the anticonvulsant action of phenytoin and significantly increased the beneficial action of diazepam against maximal electroshock and pentylenetetrazole‐induced convulsions in a mouse model.     

Anticonvulsant activity of some 4-aminobenzanilides

A series of 4-aminobenzanilides derived from ring-alkylated anilines were prepared and evaluated for anticonvulsant activity. These benzanilides were prepared in the course of studies designed to determine the relationship between the benzamide structure and anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and metrazole (pentylenetetrazole) and in the rotorod assay for neurologic deficit. All of the 4-aminobenzanilides showed activity at doses of 300 mg/kg against maximal electroshock seizures (MES). The 4-aminobenzanilide derived from 2,6-dimethylaniline (8) was the most potent anti-MES compound with an ED50 of 2.60 mg/kg and a protective index of 5.77 (PI = TD50/ED50). The activity profile for 8 compares quite favorably with that for phenobarbital and phenytoin in the same assays.     

Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat

The current studies further investigated the effects, in animal models of anxiety, of novel putative anxiolytic and anxiogenic compounds believed to induce their effects by actions at the GABA-benzodiazepine receptor complex. It was expected that the results would also provide further validation for a novel test of anxiety based on the ratio of open to closed arm entries in an elevated plus maze in the rat. The novel putative anxiolytics CL 218,872 (10-20 mg/kg) and tracazolate (5 mg/kg) significantly elevated the percentage of time spent on the open arms of an elevated plus-maze, consistent with their anxiolytic activity in several other animal tests. Also consistent with results from other animal tests, no anxiolytic activity was observed for the phenylquinoline PK 8165 (10-25 mg/kg), the 3,4-benzodiazepine tofisopam (25-50 mg/kg), or buspirone (0.5-20 mg/kg). The benzodiazepine receptor inverse agonists FG 7142 (1-5 mg/kg) and CGS 8216 (3-10 mg/kg) had anxiogenic activity in this test, as did the atypical benzodiazepine Ro 5-4864 (1-5 mg/kg). Interestingly, however, the benzodiazepine receptor antagonists Ro 15-1788 (10-20 mg/kg) and ZK 93426 (5-10 mg/kg) had no anxiogenic activity in this test.     

CGS 9896: A nonbenzodiazepine,nonsedating potential anxiolytic

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.     

Anticonvulsant properties and bio-guided isolation of palmitone from leaves of Annona diversifolia

The activity-guided fractionation of the ethanol extract of leaves of Annona diversifolia Saff., led to the isolation of palmitone (16-hentriacontanone) as the only anticonvulsant active compound. This aliphatic ketone was highly effective to diminish pentylenetetrazole (PTZ)-induced clonic-tonic seizures and toxicity. Also, it produced a prolongation of the latency for onset of seizures and a reduction of the death rate produced by 4-aminopyridine (4-AP) and bicuculline (BIC). However, it was inactive to inhibit the kainic acid (KA)- and strychnine (STC)-induced seizures. Palmitone did not produce motor incoordination and loss of righting reflex which are used as signs of neurological impairment. Palmitone (ED50 = 1.85 mg/kg) proved to be a more potent antiepileptic drug against the PTZ-induced seizures than etosuximide (ED50 = 59.6 mg/kg), sodium valproate (ED50 = 63 mg/kg), and carbamazepine (ED50 > 300 mg/kg) and it was only four-fold less potent than diazepam (ED50 = 0.48 mg/kg). The pharmacological profile of palmitone suggests that this compound could be acting on the GABAergic inhibitory system.     

Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor.

Tiagabine (NO-328) (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl]nipecotic acid, hydrochloride) is a new centrally acting GABA uptake inhibitor. The anticonvulsant activity of tiagabine was evaluated against seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), pentylenetetrazol, bicuculline, maximal electrostimulation (MES), or high intensity sound. The sedative actions of tiagabine were evaluated in tests for traction, rotarod performance and exploratory behavior. Finally, interoceptive properties of tiagabine were assessed using diazepam-, CGS 9896-, pentylenetetrazol-, or amphetamine-discriminating rats. Tiagabine was an effective anticonvulsant in doses which did not produce sedation or motor debilitation, although it was not potent against MES. In a manner similar to other anti-epileptic drugs, tiagabine potentiated dopaminergic function (methylphenidate-induced gnawing in mice) although it did not substitute for amphetamine in amphetamine-trained animals. Furthermore, although tiagabine antagonized DMCM-induced convulsions, it exhibited neither CGS 9896 or diazepam-like interoceptive effects, nor did it block (or potentiate) pentylenetetrazol-discrimination. Thus, GABA uptake inhibition represents a novel rationale for a valproate-like anticonvulsant drug therapy.     

2-Phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides as non-benzodiazepine anticonvulsants and anxiolytics.

A series of 2-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides were designed and synthesized as non-benzodiazepine anxiolytics based on a molecular disconnection of a typical 1,4-benzodiazepine (BZD). A number of these compounds showed submicromolar potency in a [3H]benzodiazepine binding assay in vitro and good potency in protecting rodents against pentylenetetrazole-induced seizures. Compound 84 appears to be a selective anticonvulsant (pentylenetetrazole) agent when tested against a profile of chemically and electrically induced seizures in mice. In addition, compound 148 appears to be a selective anxiolytic/hypnotic agent on the basis of biochemical and pharmacological characterization. It appears to be a full BZD agonist as assessed by GABA shift ratio and to be effective in punishment and nonpunishment animal models of anxiety. In addition, it shows a lower side-effect profile than diazepam as assessed by rotorod neurotoxicity and potentiation of ethanol-induced sleep time in mice. The chemistry and structure-activity relationships of this series is discussed.     

Anticonvulsant activity of some 4-aminobenzamides

A series of 4- aminobenzamides of some simple primary and secondary amines were prepared and evaluated for anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole ( metrazole ) and in the rotorod assay for neurologic deficit. For those N-alkyl amides tested, 4-amino-N- amylbenzamide (6) was the most potent against maximal electroshock seizures (MES): ED50 = 42.98 mg/kg; however, the N- cyclohexylbenzamide (8) showed the greatest protective index (PI = TD50/ED50), 2.8. The introduction of a second aromatic ring produced more potent compounds, with d,l-4-amino-N-(alpha-methylbenzyl)-benzamide (12) showing the highest level of activity. This compound has an anti-MES ED50 of 18.02 mg/kg in mice when administered intraperitoneally (ip) and a TD50 of 170.78 mg/kg (PI = 9.5) in the same species. These data compare quite favorably with those for phenobarbital and phenytoin in the same assays.     

Anticonvulsant activity of 2- and 3-aminobenzanilides

A series of 2- and 3-aminobenzanilides derived from ring-alkylated anilines were prepared and evaluated for anticonvulsant activity. These benzanilides were prepared in the course of studies designed to determine the relationship between the benzamide structure and anticonvulsant effects. The compounds were tested in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazole and in the rotorod assay for neurologic deficit. The 3-aminobenzanilide derived from 2,6-dimethylaniline, 21, was the most potent anti-MES compound, with an ED50 of 13.48 mg/kg and a protective index of 21.11 (PI = TD50/ED50). The activity profile for 21 compares favorably with that for phenobarbital and phenytoin.     

Discriminative stimulus properties of chlordiazepoxide and zolpidem. Agonist and antagonist effects of CGS 9896 and ZK 91296

In previous studies the effects of CGS 9896, a pyrazoloquinoline ligand at benzodiazepine receptors, in rats trained to discriminate benzodiazepines from vehicle, have been variable. The present experiment confirmed that this compound produced responding on the drug-lever in rats trained to discriminate 5 mg/kg of chlordiazepoxide from saline, and showed that CGS 9896 did not antagonise the effect of chlordiazepoxide in this test. In contrast, CGS 9896 antagonised the stimulus properties of zolpidem (2 mg/kg), a non-benzodiazepine hypnotic, which displaces benzodiazepines from their binding sites. The drug CGS 9896 also antagonised responding on the drug-lever produced by chlordiazepoxide in rats trained with zolpidem. The beta-carboline, ZK 91296, produced effects similar to those of CGS 9896, giving rise to responding on the drug-lever in rats trained with chlordiazepoxide and antagonising the zolpidem cue. These results demonstrate the mixed agonist-antagonist effects of CGS 9896 and ZK 91296 and suggest that the stimulus properties of chlordiazepoxide and zolpidem may be mediated by different sub-types of benzodiazepine receptors.     

Sodium phenobarbitone reverses the anxiogenic effects of compounds acting at three different central sites

Sodium phenobarbitone was tested for its ability to antagonise the anxiogenic effects of compounds acting at three different central sites. These compounds were: FG 7142, a beta-carboline which acts at the benzodiazepine binding site on the GABA-benzodiazepine receptor complex; pentylenetetrazole, which acts at the picrotoxinin site on the GABA-benzodiazepine receptor complex; and yohimbine which is an antagonist at the alpha 2-adrenoceptor. The experiments were carried out in two tests of anxiety using rats. In the social interaction test (the test arena was familiar and dimly lit), FG 7142 (5 mg/kg) and pentylenetetrazole (15 mg/kg) reduced the time spent in social interaction (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone decreased locomotor activity as measured in the social interaction test, which was reversed by pentylenetetrazole (15 mg/kg). In the elevated plus-maze, FG 7142 (6.7 mg/kg) pentylenetetrazole (20 mg/kg) and yohimbine (4 mg/kg) reduced the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone significantly increased the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiolytic activity). This study, together with previous studies using other clinically-effective anxiolytic drugs, suggests that the ability of a compound to antagonise the effects of anxiogenic agents may be a useful indirect means of predicting anxiolytic activity.     

Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (compound 69/183). Part IV: other CNS effects and acute toxicity

3-[gamma-(p-Fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (centpyraquin), a potent antihypertensive and tranquillising agent, was tested for anticonvulsant, analgesic and anti-inflammatory activities in mice and for anti-emetic activity in dogs. It did not modify supramaximal electroshock seizures and failed to protect the animals against pentylenetetrazole and strychnine induced convulsions. It, however, produced some elevation in the threshold dose of strychnine. Tremorine induced tremors and salivation were not antagonised. The compound had weak analgesic activity as detected by antagonism to phenylquinone writhing and the hot plate test. It had no anti-inflammatory activity. Centpyraquin had strong anti-emetic activity against apomorphine as well as morphine. At high doses it produced fall out in the rota-rod test. The LD50 of centpyraquin in mice was 296 mg/kg i.p. and more than 1000 mg/kg p.o. and in rats it was 161 mg/kg i.p. and more than 800 mg/kg p.o. The observed CNS effects resemble those of other neuroleptics.