Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine.

Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizures (MES) in rats when given po. The differences in anti-MES activity for these analogues was not explained by differences in pKa or lipophilicity. However, the four classes of heterocycles have distinctly different calculated electrostatic isopotential maps, which may be related to optimum anticonvulsant activity.

1-(Fluorobenzyl)-4-amino-1H-1,2,3-triazolo[4,5-c]pyridines: synthesis and anticonvulsant activity.

A series of (fluorobenzyl)triazolo[4,5-c]pyridines was synthesized and tested for activity against maximal electroshock-induced seizures in rodents. The most promising compound, 14 (BW 534U87), which is a carbon-nitrogen isoster of a purine anticonvulsant, has a profile in rodents that suggests 14 will be free of emesis and useful in the treatment of seizure disorders for which phenytoin is presently indicated.

Pharmacological properties of 403U76, a new chemical class of 5-hydroxytryptamine- and noradrenaline-reuptake inhibitor.

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.

8-Amino-3-benzyl-1,2,4-triazolo[4,3-a]pyrazines. Synthesis and anticonvulsant activity.

Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.

Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion.

The synthesis of the enantiomers of bupropion, (rac)-2-tert-butylamino-3'-chloropropiophenone 1 (Wellbutrin) is described. The enantiomers were compared with the racemate in both the tetrabenazine-induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine-induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain.

The pharmacologic evaluation of locomotor activity versus inflammatory parameters in rat adjuvant arthritis.

Adjuvant-induced arthritis (AA) is an experimental model of inflammatory joint disease in the rat which mimics rheumatoid arthritis. Although paw inflammation (e.g., swelling) is commonly used to monitor the efficacy of antiarthritic drugs, a reduction in locomotor function may provide a more sensitive evaluation of "functional disability" in AA rats. The purpose of the present study was to investigate the effect of dietary therapy with prednisolone or ibuprofen on locomotor activity as well as arthritic symptoms in established AA (days 20-42). AA rats demonstrated an increase in arthritis scores, spleen weights, fibrinogen, and WBC along with a reduction in locomotor function. Prednisolone (2 mg/kg/day) exhibited a positive therapeutic effect on all these parameters. Ibuprofen (50 mg/kg/day) consistently lowered arthritis scores and fibrinogen; however, locomotor function only improved on day 35. In conclusion, the measurement of locomotor activity in concert with other experimental parameters may provide a more meaningful evaluation of disease severity or improvement in AA.

9-(2-Fluorobenzyl)-6-(alkylamino)-9H-purines. A new class of anticonvulsant agents.

Several substituted aryl and 6-alkylamino analogues of the anticonvulsant purine 9-(2-fluorobenzyl)-6-(methyl-amino)-9H-purine (1) were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. Derivatives with a second fluoro substituent in the 5- or 6-position of the aryl moiety were very active with ip ED50's that ranged from 2 to 4 mg/kg. Congeners in which the purine 6-substituent was varied among a number of alkylamino groups possessed potent activity against MES that was comparable to or several times better than phenytoin.

6-(Alkylamino)-9-benzyl-9H-purines. A new class of anticonvulsant agents.

Several 9-alkyl-6-substituted-purines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. Most compounds were prepared in three steps from 5-amino-4,6-dichloropyrimidine or in two steps via alkylation of 6-chloropurine. Potent anticonvulsant activity against MES resided in compounds that contain a benzyl substituent at the 9-position of 6-(methylamino)- or 6-(dimethyl-amino)purine. Among commonly used agents for control of seizures, this type of structure represents a new class of potent anticonvulsant agents.

Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy.

The pro-convulsant actions of theophylline and caffeine have been investigated using the hippocampal slice preparation and rats administered kainic acid or Metrazol. Both theophylline and caffeine induced the generation of epileptiform activity in the CA3 region of the hippocampal slice with convulsive dose50 (CD50) values of 3 microM respectively. Kainic acid-induced bursting in hippocampal slices was enhanced by theophylline (0.3-30 microM) and caffeine (1-100 microM). Theophylline induced burst firing in response to electrical stimulation in hippocampal area CA3 but not area CA1. Theophylline (50 mg/kg) strongly potentiated the effect of the limbic convulsant kainic acid in vivo whilst a dose of 200 mg/kg was necessary to significantly lower the threshold dose of Metrazol required to induce generalized convulsions. We conclude that alkylxanthines, probably by antagonizing the effect of endogenous adenosine, exert a pro-convulsant action in the hippocampus which preferentially promotes limbic seizures.

Animal models used in prediction of antidepressant effects in man.

The discovery of bupropion's potential antidepressant activity resulted from studies of its behavioral effects in a number of animal models of depression. These animal models and data pertaining to their selectivity for other standard antidepressant drugs are reviewed.

The pharmacologic basis for therapeutic interest in bupropion.

Bupropion, a compound chemically dissimilar to tricyclic antidepressants and monoamine oxidase inhibitors, was found to be active in animal models that are predictive of antidepressant activity in man. Bupropion was also found to be pharmacologically and biochemically distinct from tricyclics and monoamine oxidase inhibitors. Furthermore, it lacked anticholinergic activity, was not sympathomimetic, and was at least 10-fold weaker as a cardiac depressant than the tricyclic antidepressants. It was concluded that bupropion would be better tolerated and safer in man than standard therapies and that its pharmacologic and biochemical profile held out the possibility of novel antidepressant actions.

A novel inhibitor of gamma-aminobutyrate aminotransferase with anorectic activity.

1-(n-decyl)-3-Pyrazolidinone (BW357U) is a potent, selective inhibitor of gamma-aminobutyrate aminotransferase (GABA-T) in vitro and in vivo. After acute or chronic, oral or intraperitoneal administration of BW357U to rats, brain GABA levels were elevated in a dose-dependent manner. When inhibition of brain GABA-T exceeded 50%, whole brain GABA levels were elevated approximately threefold, and an anorectic effect was observed in the absence of other symptoms. This compound, because of its potency and selectivity, may be useful in studies relating to the function of GABA-containing neurons in appetite regulation.

Neurochemical and neuropharmacological investigations into the mechanisms of action of bupropion . HCl--a new atypical antidepressant agent.

In the present study, bupropion has been shown to be effective in several behavioral models predictive of antidepressant activity suggesting that it should be an effective antidepressant in man. Furthermore, the data also show that the antidepressant activity of the drug cannot be due to its ability to inhibit MAO present in brain or to increase the release of biogenic amines from nerve endings. It also appears unlikely that the weak properties of the drug as an inhibitor of catecholaminergic pumps in brain csn explain its antidepressant activity. However, the weak but selective block of dopaminergic pumps observed in vivo can be correlated with the mild CNS stimulant properties observed in rodents. Bupropion, failed to desensitize beta-adrenergic receptors in rat cerebral cortex in chronic studies and exhibited equivocal results in acute studies. These neurochemical properties of bupropion serve to distinguish it from typical antidepressants of the MAOI and tricyclic classes and suggest that it should be classified as an atypical antidepressant, whose mechanism of action must still be elucidated.

Potential anticonvulsants. 1. 5-Benzylhydantoins.

A selected group of alkoxy- and halogen-substituted 5-benzylidino- and 5-benzylhydantoins was prepared and screened for anticonvulsant activity as measured by the ability of the compound to prevent maximal electroshock and metrazol-induced threshold clonic seizures in rats. The structure-activity studies revealed 5-[3-(trifluoromethyl)benzyl]hydantoin (14) to be the most potent member of the series.

2-(Alkoxyaryl)-2-imidazoline monoamine oxidase inhibitors with antidepressant activity.

Unlike the related noncyclic amidines which are broad-spectrum cestocides, a number of 2-imidazolines substituted in the 2 position by alkoxyaryl groups were not highly active in screening tests against the mouse tapeworms Hymenolepsis nana and Oochoristica symmetrica. Certain of the 2-(4-alkoxynaphthyl)-2-imidazolines and 2-(6-alkoxy-2-naphthyl)-2-imidzolines, however, had activity interpreted as antidepressant in the mouse. This activity paralleled in vitro irreversible inhibitory activity against mouse brain MAO for those where no substitution is present on the imidazoline ring. This irreversibility probably has a different origin from that postulated to explain the irreversible MAO inhibition of proparglic, cyclopropyl, and other "chemically reactive" MAO inhibitors.