Vargha László et al. (szerk.): Beszámoló a Gyógyszeripari Kutató Intézet 10 éves működéséről 1950-1959 (Budapest, 1969)

Dr. Borsy József: Az N-(3,4,5-trimetoxibenzoil)-tetrahidrooxazin (V-7) neuroszedatív hatása

J. BORRY:

THE NEURO-SEDATIVE ACTION OF N-(3.4,5-TRIMETHOXYBENZOYLTETRAHYDROOXAZINE (COMPOUND V-7)

The compound N-3,4,5-trimethoxybenzoyl-tetrahylrooxazine (V-7) was tested by us for its neuro-sedative action and acute, subacute and chronic toxicity.

1. In mice V-7 was found to inhibit hyperactivity from orientational reflexes. This assay method revealed an ED50 value of 88,0 mg/kg for intraperitoneal, and 105 mg/kg for peroral administration, resp. From this minor difference of doses easy resorption of V-7 from the gut is inferred. On intraperitoneal administration its tranquillizing action equals that of Meprobamate, and by mouth it is twice as much active.

2. Bv means of the rotating stick method it was disclosed that V-7 disturbes coordinated motility in mice, its ED50 amounting to 145 mg/kg in that respect. Righting reflex is abolished by toxic doses only (800 to 1200 mg/kg in mice). The PD5n value is 1100 mg/kg i. p. Meprobamate already paralyses animals in subtoxic doses (235 mg/kg i. p.).

3. V-7, in a dose of 60 mg/kg i. v.. does not affect the monosynaptic patellar reflex. In spinal cat a nearly equal dose either activates or, at least, does not inhibit the polysynaptic flexor reflex. As regards reflex activity, V-7 differs from Meprobamate which is an exquisite depressant.

4. Assayed with the ,,hot plate“ method in rats, V-7 had but a mild analgetic effect. Its AD50 value, i. e., the dose causing analgesy in 50%, amounts to 135 mg/kg i- P-5. 100 mg/kg of V-7, i. p., elicits hypothermia in rats. With rising doses this effect becomes intensified.

6. Morphine analgesia in rats is potentiated by 100 mg/kg i. p., and, alike, Hexobarbital anaesthesia in rats and mice.

7. Concerning antagonizing effects, 200 mg/kg of V-7, i. p., lift up benzedrine and morphine excitement, resp., in mice. Furthermore, 50 mg/kg i. p. of V-7 prevent mescaline stereotypia in mice as caused by 60 mg/kg s. c.

8. V-7 proves moderately effective against pentamethylene-tetrázole convulsions (300 mg/kg inhibit only to 40%), in minor doses (100 mg kg) against nicotine. Even much higher doses (300 to 400 mg/kg) are ineffective on convulsions by strychnine.

9. Vomiting, provoked in dogs with a standard dose (0,05 mg/kg) of apomorphine, is in part accessible to 75 mg/kg of V-7, i. m. Latency time was in all of the animals prolonged, and frequency of retching by a 20 to 100% reduced.

10. 50 mg/kg of V-7, injected i. v., caused transient fall of blood pressure in cats narcotised with chloralose-urethane. During that effect the reflectory hypertension to bilateral carotid compression regressed by 40 to 60%, and the nictitating membrane contractions upon electrical stimulation of preganglionary fibres to the superior cervical ganglion were reduced by 26 to 40%.

11. The contractions of guinea pig intestine as caused by histamine, acetylcholine and serotonin were insensitive to 10 to 40 у/'ml concentrations of V-7.

12. The drug possesses low grade of toxicity. Its LD50 values in mice as ascertained on different routes of administration were as follows: 960 + 36,0 mg/kg. i. v., 1320 + 42,0 mg/kg i. p. and 3300 + 104,0 mg/kg p. os. To the rat nearly the same quantities proved toxic. The toxicity both upon subacute and chronic administration has turned out not less favourable.

The data furnished by our experiments corroborate that N-3,4,5-tri me t h о x у - benzoyl-tetrahydrooxazine exerts its sedative action by depressing certain cortical and subcortical areas, but at the same time leaving unaffected the spinal medulla. Some properties of it, e. g., the wide gap between its tranquillant and paralysing doses, the maintenance of the righting reflexes along with sedation, its inability of antagonizing strychnine convulsions and toxicity, the abidance of mono- and polysynaptic reflexes render V-7 a neuro-sedative drug devoid of the side-effects of ataxy and muscular weakness. This is an advantage from the prospect of using it for ,,day-time sedation“.

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