The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).

With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.

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The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.

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