Studies on the mode of action of quaternary ammonium compounds with muscle-relaxant and other pharmacological activities

Muir, Thomas C (1962) Studies on the mode of action of quaternary ammonium compounds with muscle-relaxant and other pharmacological activities. PhD thesis, University of Glasgow.

Abstract

A survey of certain aspects of the literature on neuromuscular blocking agents is given with particular reference to the study of their pharmacological and electropharmacological effects at the motor end plate, their interaction with the hypothetical receptors at this site and the derivation of mathematical equations to explain these effects. Attention was also paid to the various classifications adopted to subdivide muscle relaxants and a review given of synthetic neuromuscular blocking compounds, particularly those containing the ether oxygen link. A study has been made of the pharmacological actions of a number of synthetic bis- and polyonium compounds containing one and two ether oxygen functions and of three sulphur-containing bis-onium derivatives. Attempts were made to draw structure-action relationships among these drugs and to assess, where possible, the contribution of the ether oxygen function to the neuromuscular blocking activity observed. The methods employed consisted of the conventional techniques commonly used to evaluate neuromuscular blocking activity using the cat, rabbit, hen, chick, mouse and frog together with the method described by Ariens, using the frog rectus abdominis muscle and based on drug-receptor interaction. The activity of the new compounds on the cardiovascular system, on autonomic ganglia, on respiration and on the isolated rabbit heart were also investigated. From these experiments, the compounds investigated were divided into depolarizing and non-depolarizing neuromuscular blocking agents. With the exception of the frog, where the reverse order of potency was true, the ether containing polyonium compounds were less potent than the corresponding non-ether analogues. These results were confirmed and extended by means of the Ariens' technique and the affinities and/or intrinsic activities of certain of the compounds calculated. From the results obtained using more conventional methods, attempts were made to derive structure-action relationships based on considerations of the nature of the alkyl substituents on the onium groups, the number and character of the onium groups and the nature and length of the inter-onium chain. Due to the chemical dissimilarities among the compounds, the derived relationships were empirical and resort was made to drug-receptor interaction as a means of placing their pharmacological activity on the common bases of affinity and intrinsic activity. By this means, the effect of the ether-oxygen function in influencing the affinity of neuromuscular blocking compounds was established. None of the compounds investigated appeared to possess properties which might lead to their clinical use. The possibility that anti-cholinesterase effects contributed in whole or in part to depolarizing activity prompted the investigation of a number of bis- and polyonium neuromuscular blocking agents for anti-acetylcholinesterase activity. Anti-acetylcholinesterase activity was estimated manometrically using a cholinesterase preparation from rat brain and potency calculated as the pI50 value, None of the compounds tested was more potent than eserine or neostigmine. The greater anti-acetylcholinesterase effect of depolarizing compared to non-depolarizing agents was confirmed, but a direct correlation between this action and depolarizing properties could not be esteblished. The results of the investigation are not incompatible with the view that the cholinergic receptor and the anti-acetylcholinesterase enzyme surfaces are probably not identical.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: J J Lewis
• Keywords: Pharmacology
• Date of Award: 1962
• Depositing User: Enlighten Team
• Unique ID: glathesis:1962-73527
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jun 2019 08:56
• Last Modified: 14 Jun 2019 08:56
• URI: https://theses.gla.ac.uk/id/eprint/73527