The Inhibition of Amine Oxidase and the Central Stimulating Action of the Stereoisomeric Amphetamines and 1‐phenylethylamines

Abstract

The stereoisomers of amphetamine and 1-phenylethylamine have been studied in the rat both as central stimulants and as inhibitors of amine oxidase from brain, liver, and kidney. There was no correlation between these two effects; thus it is unlikely that the central stimulating action of amphetamine is due to inhibition of amine oxidase.It is known that species differences exist in the pattern of substrate and inhibitor specificities Pratesi and Blaschko (1959) showed that, for a substrate as well as for an inhibitor, the presence of a centre of asymmetry in the molecule may confer different affinities (or rates of oxidation) on the. two enantiomorphs, and also that this depends on the source of the enzyme. Mann and Quastel (1940) suggested that central stimulation by amphetamine might be due to inhibition of amine oxidase. However, although in rabbit and man (+)-amphetamine (dexamphetamine) is a stronger stimulant than the (-) form, Pratesi and Blaschko (1959) have shown that the two stereoisomers are equally active as inhibitors of rabbit liver enzyme.To test the idea that amphetamine owes its analeptic properties to its inhibitory action on amine oxidase, it was clearly necessary to use amine oxidase from the same species as that used for the pharmacological experiments. It was also desirable to use amine oxidase from the brain in preference to liver, because the patterns of substrate and inhibitor specificities might vary in different organs.The present paper describes studies in the rat on dexamphetamine and (-)-amphetamine and (+)-and (-)-l-phenylethylamine as central stimulants and as inhibitors of amine oxidase from different organs (brain, liver, kidney). We studied 1-phenylethylamine because Pratesi and Blaschko (1959) found it to be a stronger inhibitor of the rabbit and cat liver enzyme than amphetamine; moreover 1-phenylethylamine had not yet been studied as a central stimulant. We have also studied the activity of dexamphetamine and (-)-amphetamine on amine oxidase from rabbit brain. METHODSThe two amphetamines and 1-phenylethylamines used in our experiments were prepared by Dr. A. La Manna of our Institute. All these substances were obtained as the hydrochlorides. The signs (+) and (-) refer to the rotation of the hydrochlorides in aqueous solution.In some pharmacological experiments we have also used the sulphate of dexamphetamine.Toxicity was studied in mice weighing 20 to 25 g. by injecting aqueous solution of the substances intraperitoneally. The animals were placed in groups of two or three in glass cages and observed for 24 hr.Central stimulant activity was studied by measuring the duration of central depression in rats treated with chloral hydrate; the substance under examination was injected 5 min. after the beginning of the depression.The sources of amine oxidase were rat liver, brain, and kidney, and rabbit brain. The fresh tissue was ground with sand; 2 ml. of 0.067 M-sodium phosphate buffer at pH 7.4 were added for each 1 g. of fresh tissue and the sand was then removed by centrifugati...

Studies on Tetrahydroisoquinolines (Thi) (I) Bronchodilator Activity and Structure-Activity Relationship

“…For example, when tested with the iso lated tracheal muscle preparation of calf, the pD,-values of norepinephrine, and its N methylated (E), ethylated, isopropylated (Iso), and t-butylated analogues were 5.8, 6.7, 7.2, 7.5 and 7.6 respectively (18). It was also reported (22,27) that N,N-dimethylated norepinephrine maintained the adrenergic activity but at a decidedly lower level, and the N,N,N-trimethylated analogue was practically devoid of the activity. Based on these facts, it is generally accepted that the secondary nitrogen atom carrying a bulky sub stituent is essential for the activity.…”

“…The structure-activity relationship of catecholamines, the representative 9-adrenergic stimulants, has been studied for many years by several investigators (11)(12)(13)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Based on the results of these investigations, it is generally accepted that the catecholic hydroxyl groups at position 3 and 4 are essential for manifestation of the Q-adrenergic activity (11-13).…”

General Pharmacology of Amphetamine-Like Drugs

“…review by BLASCHKO, 1952), a number of studies have confrrmed this finding for a number of species, tissues, and substrates. Thus, preparations from rat, mouse, and rabbit brain (GRANA and LILLA, 1959;GLOWINSKI et al, 1966a;GREEN, 1971;MÖLLER-Nielsen and DUBNIK, 1970;MORGAN et al, 1972b), rat, rabbit, and guinea pigliver (ORzEcHOWSKI, 1941;PRATESland BLASCHKO, 1959;GRANA and LILLA, 1959;FuLLERand WALTERS, 1964;PARMAR, 1966;NIELSEN etal., 1967;YAsUNoBuand 01,1972), rat kidney (GRANA and LILLA, 1959), rat heart (LEITZ and STEFANO, 1971), pig plasma (BUFFONI and DELLA CORTE, 1972), and human brain and salivary glands (BLASCHKO and STRÖMBLAD, 1960) have been used as enzyme sources. Concentrations of amphetamine ranging from 10-5 -10-2 M seem to be needed for inhibition of deamination of typical MAO substrates: adrenaline, noradrenaline, tyramine, oxedrine, kynuramine, benzyl amine, serotonin, tryptamine, and phenylethylamine.…”

Steric Aspects of Adrenergic Drugs

“…It wasconcluded thatcentraleffects of(+)-and (-)-amphetamine, (-)-ephedrine, and (+)-ephedrine possess large indirect components in their activity while those of (+)-pipradrd, (.-)-norephedrine, and (+)-norpseudoephedrine are mainly direct. The effects of the optical isomers of amphetamine were also investigated on brain dopamine levels (305, 306), tissue respiration (307), and liver monoamine oxidase inhibition (284). However, both forms of amphetamine isomers produced similar results, indicating that these effects are not causally related to the central effects.…”

“…Although stereochemical substrate specificity was not detected in the early semipurified enzymatic preparations (283)(284)(285)(286), it is now demonstrated that indeed these enzymes do show selectivity for the (-)-isomers of norepinephrine, epinephrine, and rn-octopamine which are better substrates than their corresponding (+)-isomers (287). Kynuramine oxidation by rat liver monoamine oxidase was inhibited more by (+)-isomers (2s) of amphetamine, 2,4-dichloroamphetamine, 4-chloro-N-methylamphetamine, than their corresponding (-)-isomers (288).…”