A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha-benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

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It has been suggested that heptaminol and methylheptaminol should be used as myocardial stimulants because they have cardiotonic actions similar to those of cardiac glycosides. However, as these aliphatic amines show definite sympathomimetic effects, the mechanism of their actions on the heart was investigated, in order to determine whether digitalis-like properties are involved in these effects. The pattern of pharmacological actions of heptaminol and methylheptaminol was compared with that of catechol amines, tyramine and k-strophanthin. The influence of atropine, hexamethonium, cocaine and reserpine was also investigated. The results show that both heptanolamines have a long-lasting cardiostimulant action which is abolished by cocaine and absent in reserpine pretreated animals. The pharmacological activity of these drugs may be entirely attributed to an indirect sympathomimetic action of the tyramine type, probably due to release of endogenous catechol amines. None of the experimental findings is consistent with the alleged digitalis-like action of these compounds.Among the aliphatic amines, the heptylamines with an alcoholic function on carbon two have been the object of a more detailed pharmacological study, as they show cardiostimulating properties which are particularly intense and long-lasting. The two most active compounds of the series, heptaminol (6-amino-2-methyl-2-heptanol; 2831 RP; Heptamyl; Cortensor) and methylheptaminol (6-methylamino-2-methyl-2-heptanol; 3738 RP; Aranthol), have been employed in the therapy of various clinical conditions including heart failure. Their use in heart failure is based on the experimental work of Loubatieres (1949aLoubatieres ( & b, 1951 and Loubatieres, Bouyard, Macabies & Mouralis (1949), who observed digitalis-like cardiotonic effects on the cat papillary muscle preparation fatigued by repeated electrical stimulation and on the dog ventricle ii situ. Coraboeuf & Boistel (1953), recording the action potentials of cardiac tissue by means of intracellular microelectrodes, concluded that heptaminol shows powerful cardiotonic effects.These heptanolamines, however, exhibit pharmacological actions which may be interpreted as depending on an activation of sympathetic receptors (Jackson, 1947;Walton, Belkin & Brodie, 1947;Huggins, Handley & La Forge, 1949;Marsh & Herring, 1951; Garrett, 1954; v. Haxthausen, 1955;Hille & Teske, 1957). It thus seems necessary to characterize the nature of their cardiostimulating action, in order to ascertain whether, as well as their sympathomimetic action, there is also a digitalis-like component which may significantly contribute to the cardiac effects.

Tissue noradrenaline content as well as uptake and metabolism of tritiated exogenous noradrenaline were studied comparatively, in vitro in mesenteric arteries, and in saphenous veins of normotensive and perinephritic hypertensive dogs. The influence of cocaine, iproniazid and 3’-4’-dihydroxy-2-methyµ-propiophenone (U-0521) on these variables wasalso investigated. The concentration of (–)-7-³H-noradrenaline used was 1.084 µM. No changes were observed in noradrenaline content, uptake and metabolism in saphenous vein strips obtained from normotensive or hypertensive animals. However, in mesenteric artery strips obtained from hypertensive dogs, a marked reduction in endogenous noradrenaline content was observed as well as a reduction in noradrenaline accumulation (20 weeks after surgery). The deamination pattern was also modified in these strips: the formation of DOPEGwas markedly diminished and the formation of DOMA was increased. These results agree well with the degeneration of the sympathetic innervation of the mesenteric arteries of hypertensive dogs described by Azevedo et al. (1981).

This paper presents the results of experiments in which some cardiovascular parameters of the anaesthetized dog were recorded, in an attempt to elucidate the mechanisms involved. METHODSSeventeen mongrel dogs of either sex weighing between 8 and 18.5 kg were anaesthetized with pentobarbitone sodium (30 mg/kg, intravenously) and both vagi were cut in the neck. Blood pressure was measured with a Statham transducer (model P23AA) and a carrier preamplifier from a cannula in the left carotid artery. During artificial ventilation, thoracotomy was performed, a pericardial cradle was prepared and a Walton-Brodie strain gauge arch was sutured to the right ventricle and connected to another carrier preamplifier. After heparinization (5 mg/kg followed by 2 mg/kg at 45 min intervals), blood flow in the femoral artery was measured by means of a Shipley-Wilson type rotameter (Blood Flow Assembly).All measurements were recorded on a Physiograph Six (E & M Instrument Co.). Heart rate was measured from the original tracings.After obtaining control responses to intravenous injections of suitable doses of adrenaline, noradrenaline and isoprenaline and to close intra-arterial injections of adrenaline and isoprenaline (0.25 to 16 alg doses), the animals were treated with phenoxybenzamine (5 mg/kg) and these procedures repeated 30 min later. Catecholamine administration was once more repeated some minutes after pronethalol (5 mg/kg) was given. Six dogs received, instead of injections, adrenaline or noradrenaline by intravenous infusion from a constant rate pump (Braun), over a period of 4 min (5 ,ug/kg/min). In some animals 883 F (diethylaminomethylbenzodioxane hydrochloride) (5 mg/kg) was administered at the end of the experiment.Drugs. Phenoxybenzamine hydrochloride (Smith, Kline & French) was dissolved to a concentration of 10 mg/mi. in propylene glycol acidified by concentrated hydrochloric acid in order to obtain * Since deceased.