Choline Phenyl Ethers as Inhibitors of Amine Oxidase

Abstract

The parent compound of this series, choline phenyl ether, < O.CH2CH2N(CH3)3was first studied by Hunt and Renshaw (1929), who showed it to be a powerful ganglion stimulant. , while investigating the nicotine-like stimulant activities of nuclear-substituted choline phenyl ethers, noticed that choline p-tolyl ether (TM6), which had a very weak ganglion-stimulant action, potentiated the effects of adrenergic nerve stimulation, as indicated by an increase in the tone and amplitude of contraction of the nictitating membrane in response to preganglionic stimulation of the cervical sympathetic nerve (Fig. 1). The compound was also found to potentiate the effects of injected adrenaline and noradrenaline on the blood pressure ( Fig. 2) and on the nictitating membrane of cats. It seemed unlikely that these potentiations were related to actions at ganglia; they could, however, be accounted for-at least in part-if the compound delayed the destruction of adrenaline and noradrenaline. Work on adrenaline inactivation was then in progress in the laboratory, and we were soon able to show that choline p-tolyl ether was in fact a powerful inhibitor of adrenaline inactivation in vitro, and that this was because it inhibited amine oxidase. Other related compounds which produced similar potentiating effects were also shown to inhibit amine oxidase.Whether amine-oxidase inhibition fully accounts for the phenomena which prompted us to look for it will not be considered further here. But, having been led to the discovery of these new inhibitors, it seemed worth while to make a quantitative study of their relative potencies, and to see if we could determine any relations between chemical structure and amine-oxidase-inhibitory activity. This paper describes that work.Present address: Royal College of Medicine, Baghdad, Iraq.By a method about to be detailed, we have sought to correlate amine -oxidase -inhibitory activity and chemical structure in the parent compound and in eighteen nuclear-substituted choline phenyl ethers, and in some related compounds in which the cationic head was modified, and the chain length and structure were altered. We have also compared the activities of these new drugs with well-known inhibitors of amine oxidase such as ephedrine, amphetamine, and cocaine. The nature of the inhibition-whether competitive or non-competitive-has also been determined.Amine oxidase has usually been studied in vitro by manometric methods-for example, by Hare (1928); Blaschko, Richter, and Schlossmann (1937b);Philpot (1940);and Tickner (1951). Blaschko, Richter, and Schlossmann (1937a)

Adrenergic Neuron Blocking Drugs

“…It was related to choline p-tolyl ether bromide (TM-6) ( Fig. 1) which was an inhibitor of monoamine oxidase (BROWN and HEY, 1956;BAIN, 1960). Xylocholine was the first compound reported to antagonize the response of effector organs to postganglionic nerve activity without simultaneously antagonizing their response to injected catecholamines (HEY and WILLEY, 1954;EXLEY 1957EXLEY , 1960.…”

Some Factors Affecting the Neuron Blocking Action of Guanethidine, Xylocholine, Bretylium and Debrisoquin

“…A possibility may be that although these three neuron blockers are taken up by the adrenergic neuron through a mechanism distinct from the one concerned with the uptake of NA, a suggestion already made for bretylium (19,22), intraneuronally accumulated NA resulting from exposure to high concentrations of NA may not allow effective intraneuronal concentrations of the three neuron blockers to be built up. Debrisoquin, bretylium and xylocholine are known to possess MAO in hibitory action (13,23,24). Effective reduction of the intraneuronal concentration of bretylium during exposure to tyramine has been explained as due to a competition between tyramine and bretylium at the enzyme MAO and a number of sites besides the enzyme MAO (23).…”

The effect of inhibition of amine oxidase in vivo on administered adrenaline, noradrenaline, tyramine and serotonin

“…This inhibition of monoamine oxidase in vivo is said to occur in cats also. The compound choline-p-tolyl ether bromide (TM 6) has been shown to be an effective inhibitor of guinea-pig liver amine oxidase activity in vitro (Brown & Hey, 1956) and to modify the excretion products of tyramine in rats and mice (Schayer, 1953) and of tryptamine in mice (Schayer, Wu, Smiley & Kobayashi, 1954) in a manner which is presumed to indicate such activity. …”