Effects of LU-111995 in three models of disrupted prepulse inhibition in rats.

LU-111995 is a novel antipsychotic drug in clinical development. It has a clozapine-like receptor profile and affinities for dopamine D(4) and 5-hydroxytryptamine(2A) receptors. The effects of LU-111995 were examined in three models of disrupted prepulse inhibition (PPI) in rats. The first model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the dopamine agonist apomorphine. LU-111995 significantly reduced the effect of apomorphine on PPI but also slightly increased PPI by itself. Thus, the increases in PPI were not specific to the animals treated with apomorphine but reflected an effect of LU-111995 on PPI. LU-111995 also attenuated the apomorphine-induced increase in startle reactivity. The second model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the psychotomimetic phencyclidine (PCP). LU-111995 significantly blocked the PCP-induced increase in startle reactivity but did not alter the PPI-disruptive effects of PCP. The third model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by isolation-reared rats tested as adults. Isolation rearing of rats produced deficits in PPI. LU-111995 reversed the isolation rearing-induced deficit in PPI without having any significant effect on PPI in socially reared rats. In summary, LU-111995 exhibits potential antipsychotic-like activity in two models of disrupted PPI. It remains to be elucidated whether its effects on PPI can be attributed to a blockade of single dopamine and 5-hydroxytryptamine receptor subtypes, especially D(4) and 5-hydroxytryptamine(2A), or a combination of both.

A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy.

Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA receptor-selective LU 112313 was the least selective compound in this model, indicating that non-NMDA antagonists acting at both AMPA and kainate receptors are more effective in this model than AMPA receptor-selective drugs. Three of the novel compounds, i.e. LU 97175, LU 115455 and LU 136541, exerted potent anticonvulsant effects without inducing motor impairment in the rotarod test. This combination of actions is thought to be a prerequisite for selective anticonvulsant drug action.

Inhibition of monoamine oxidase type A, but not type B, is an effective means of inducing anticonvulsant activity in the kindling model of epilepsy.

The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the kindling model of epilepsy: 1) L-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3, 4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than L-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3, 4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the kindling model with a similar potency as L-deprenyl. In contrast to esuprone and L-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the kindling model; this substantiates the previous notion that the anticonvulsant activity of L-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy.

Tricyclic epines. Novel (E)- and (Z)-11H-dibenz[b,e]azepines as potential central nervous system agents. Variation of the basic side chain.

The synthesis and pharmacological activity of new (E),(Z)-[6-(alkylamino)-11H-dibenz[b,e]azepin-11- ylidene]acetonitriles 12-45 and (E),(Z)-[6-(aminoalkoxy)-11H-dibenz[b,e]azepin-11-ylidene] acetonitriles 46-51 are described. The introduction of the cyanomethylene group into the 11-position of the 11H-dibenz[b,e]azepine framework has been carried out by a Wittig-Horner reaction under mild conditions. The (E),(Z) isomers were separated by fractional crystallization, assignment being achieved by X-ray analysis. A number of (E),(Z)-[6-(alkylamino)-11H-dibenz-[b,e]azepin-11-ylidene] acetonitriles (12, 14, 16, 20) show potent neuroleptic activity (2-7 times that of clozapine) in animal tests. The screening included tests for sedative and anticholinergic activity in mice, apomorphine and tryptamine antagonism in rats, and muscle-relaxing activity in rabbits. The divergence in the activity profile in the case of the separated (E),(Z) isomers has been observed as an interesting new aspect: the (Z) isomers show a significantly higher sedative and muscle-relaxant activity, whereas the (E) isomers possess a higher anticholinergic efficacy and somewhat greater apomorphine antagonism. Broad changes in the basic side chain were made in order to investigate structure-activity relationships. The important geometrical parameters for the molecules, obtained by X-ray analysis, were compared with the corresponding features in dopamine agonists and antagonists.

Pharmacological studies on propafenone and its main metabolite 5-hydroxypropafenone.

The new antiarrhythmic drug propafenone and its main human metabolite 5-hydroxypropafenone were investigated for antiarrhythmic, local anaesthetic, Ca++-antagonistic and beta-adrenoceptor blocking effects as well as for their activity on the central nervous system. In isolated organs (guinea-pig atria, rat aortic strips) 5-hydroxypropafenone had a smaller effect on the maximum following frequency, a greater negative inotropic effect, a greater Ca++-antagonistic effect and a very distinctly weaker beta-adrenoceptor blocking effect than propafenone. Consistent with its antiarrhythmic potency in vitro, intra-cutaneous 5-hydroxypropafenone had a smaller local anaesthetic effect in the guinea pig wheal. In contrast to these findings 5-hydroxypropafenone showed a stronger antiarrhythmic potency in vivo (rat and dog), as demonstrated on the aconitine- and infarction arrhythmias. In addition, in His bundle studies 5-hydroxypropafenone caused a more marked prolongation of the conduction time in atria, AV-node and His-Purkinje system. In vivo the beta-adrenoceptor blocking effect of 5-hydroxypropafenone (isoprenaline tachycardia, rat) was smaller than that of propafenone. The difference between the in vitro and in vivo potency of 5-hydroxypropafenone may be explained by differences in pharmacokinetics, e.g. by a smaller distribution volume compared to propafenone. CNS effects were investigated due to local anaesthetic properties of the substances tested. As indicator of CNS activity anticonvulsant effects, detectably beneath convulsion-inducing doses, were determined in rats (max. electroshock seizures). The results show low CNS activity of propafenone which is even lower for the metabolite but which is distinctly higher for lidocaine and - related to the antiarrhythmic potency - for flecainide, too.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology of amezinium, a novel antihypotensive drug. VI. Effect on central nervous functions.

4-Amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in this study briefly called amezinium, was tested for possible central effects taking particular account of the mechanisms of action found for this substance in other studies. 1. The most conspicuous action of amezinium was in modifying reserpine-induced ptosis and reserpine-induced hypothermia. When amezinium is given before reserpine, the ED50 values are 0.15 and 3.9 mg/kg p.o. for both mouse and rat. These effects can be explained by a peripheral site of action since peripheral sympathomimetic effects can also be demonstrated in this dose range. Higher doses (10 mg/kg and upwards p.o.) were required to abolish reserpine-induced hypothermia 17 h after reserpine administration, an effect which probably requires a central site of action. But for imipramine, desipramine and pargyline the effective doses are the same in both experimental models (administration before and after reserpine, respectively). 2. Amezinium potentiated the effect of a threshold dose of L-dopa. Based on the central symptoms, higher doses (10 mg/kg p.o.) were also required for this effect. 3. With blood pressure increasing doses, the sleeping-waking pattern was modified in that duration and number of REM-episodes were reduced; in cats there was no parallel increase of wakefulness whilst in rats there was a slight relative increase of wakefulness. 4. Amezinium, particularly at high doses (46.4 mg/kg and upwards), exhibited a central depressant effect on the spontaneous behaviour of mice and rats and on orientational hyperactivity of mice. Based on the modification of aggregation toxicity, the effect of methamphetamine was reduced. In no dose range was there any evidence of methamphetamine-like effects (increase of motor activity, inhibition of food intake and increase of aggregation toxicity). 5. Amezinium did not affect the duration of hexobarbital anaesthesia or the coordination of mice on a rotating rod. 6. The acute toxicity of amezinium in mice and rats was low. The oral LD50 for mice was 1630 mg/kg and for rats 1410 mg/kg.

[Pharmacological investigations of 4'-fluoro-4-(4-methyl-peperidono)-butyrophenone with respect to its sedative and sleep-inducing properties (author's transl)]. / Pharmakologische Untersuchungen zur sedativen und schlafanstossenden Wirkung von (4'-Fluor-4(4-methylpiperidino)-butyrophenon (Melperon)

The butyrophenone melperone (Eunerpan) in mice and rats caused a prominetn inhibition of spontaneous activity, whereas cataleptogenic and apomorphine-antagonistic properties were less pronounced. In rats the sleep-cycle was altered: decrease of wakefulness, increase of slow-wave sleep and a moderate reduction of rapid eye movement-(REM) sleep. In contrast to thioridazine and chlorpromazine the effect lasted only for 4 h, followed by a slight REM rebound. In rabbits melperone caused a decrease of muscle tone and with somewhat higher doses an inhibition of the arousal-reaction. As seen by the computerized spontaneous cortical EEG, dosages below 1 mg/kg caused a shift of the dominant frequency from theta- to delta-rhythm and an increase of power. Therefore the neuropharmacological pattern of the butyrophenone melperone is closely related to those of thioridazine or chlorpromazine, without, however, having their long action.