Biologically active thionapthen derivatives and an investigation of the effects of some volatile anaestethics on the muscle relaxant actions of tubocurarine

This thesis describes an investigation of the pharmacological properties of a series of thionaphthen compounds and the effects of certain volatile substances on the muscle relaxant actions of tubocurarine. The thionaphthen compounds are the isosteres of gramine and its analogues differing in the replacement of -NH- by a sulphur atom. These compounds fall logically into four groups:- Group A. Gramine-like isosteres. Group B. Quaternary gramine-like isosteres. Group C. Isosteres of 5-hydroxyisotryptamine. Group D. 5-amino-isogramine-like isosteres. The work was undertaken to investigate whether or not the thionaphthen compounds were more or less specific in their actions than the corresponding indole compounds as this information might be used to obtain further information on the existence, or otherwise, of specific receptors for the indole derivatives. Experiments Experiments were carried out using isolated smooth muscle preparations and intact animals. An additional study was also made using Ariens' technique. Experimental evidence suggests that the thionaphthen compounds investigated were unselective in their pharmacological actions and many of them not only antagonized 5-hydroxytryptamine, histamine and acetylcholine on the isolated guinea pig ileum but at higher concentrations, they themselves exhibited a stimulant action on this tissue. This stimulant response was partly or completely antagonized by lysergic-acid diethylamide, atropine and mepyramine. In contrast to the anti-5-hydroxytryptamine properties on the isolated guinea pig ileum, rat uterus and isolated perfused rat headquarters, many of the thionaphthen compounds potentiated the actions of 5-hydroxytryptamine on the isolated rat fundus strip. The gramine-like isosteres (Group A) reduced the blood pressure level of the anaesthetized cat or rat whereas the quaternary salts of the gramine-like isosteres, the isosteres of 5-hydroxyisotryptamine and the 5-amino-isogramine-like isosteres (Groups B, C and D) caused no change, or a rise in the blood pressure level. None of the compounds investigated influenced the pressor response to adrenaline or noradrenaline. On the other hand, many of the compounds antagonized the vasoconstriction caused by adrenaline, noradrenaline or 5-hydroxytryptamine on the isolated perfused rat hindquarters. The results obtained using Ariens' experimental procedure indicated that many many of the compounds exhibited a purely non-competitive antagonism to 5-hydroxytryptamine. From the data presented, it was concluded that the application of the concept of bioisosterism with respect to the thionaphthen compounds studied has failed to produce derivatives of similar biological activity and also indicates that the thionaphthen compounds investigated in this thesis were unselective in their pharmacological actions when compared to the related indolic compounds. Studies of the effects of a group of volatile liquid anaesthetics and of nitrous oxide upon the muscle relaxant actions of tubocurarine were made using the spinal cat. A known concentration of the vapour in oxygen was administered to the animal and the effect on the height of contraction of the gastrocnemius muscle both in the absence and in the presence of tubocurarine was observed. It was concluded that, with the exception of tetrahydrofuran and ethylene glycol dimethyl ether, all the compounds potentiated the neuromuscular block produced by tubocurarine. Some exhibited a muscle relaxant action themselves. Di-isopropyl ether was the most potent in this respect. The potentiating action on tubocurarine was independent of the muscle relaxant action. Thus, although the halogenated hydrocarbons slightly increased the magnitude of the muscular contraction, they potentiated the neuromuscular block produced by tubocurarine. The potentiating action was not considered to be due to the presence of the ether oxygen link or related to the oil/water solubility ratio. The effect effect can most logically be attributed to their preferential adsorption at sites of loss thus enabling tubocurarine to gain greater access to the active receptor sites. It was also suggested that the loss of intracellular potassium might be a contributing factor