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The article presents a short review of some of the properties of the acetylenic inhibitors of monoamine oxidase currently under investigation: clorgyline, (-)-deprenyl, pargyline and 5-508. Their substrate-selective inactivation, mechanism of inhibition, titration and pharmacology with respect to monoamine oxidase are critically discussed.In 1968, Johnston showed that the irreversible acetylenic inhibitor clorgyline (N-methyl-N-propargyl-3-(2,4-dich1orophenoxy)-propylamine) inhibited the oxidative deamination of 5-hydroxytryptamine by rat brain monoamine oxidase (MAO, monoamine 0,: oxidoreductase (flavine containing), EC 1.4.3.4) at concentrations that were much lower than were required for the inhibition of benzylamine oxidation (Johnston 1968). When tyramine was used as substrate, a biphasic pattern of inhibition was found. Such a result has been found for a number of tissues, including the rat liver (Hall et al 1969, see Fig. I). Johnston (1968) suggested that these results were due to the presence of two forms of monoamine oxidase, which are now generally termed MAO-A and -B, where the -A form is sensitive to inhibition by clorgyline, and the -B form more resistant to inhibition. This conclusion was reinforced by the introduction of the MAO-B selective inhibitor (-)-deprenyl (phenyl-isopropy I-methyl-propinylamine) (Knoll & Magyar 1972) and its more potent analogue 5-508 (N-methyl-N-propargyl-(I-indany1)-ammonium hydrochloride) (Knoll et a1 1978). The structures of the compounds are given in Fig. 2. In addition, a variety of agents, ranging from the tricyclic noradrenaline uptake inhibitors to local anaesthetics, have been found to inhibit M A 0 activity in a substrate-selective manner (for review, see Fowler et a1 1978).In this article, the most commonly used substrateselective inhibitors, the acetylenic inhibitors of which clorgyline and (-)-deprenyl are the most well known, have been reviewed with respect to their properties, since it has been these compounds that have provided the main impetus for research in MA0 over the last decade. Substrate-specificity of monoamine oxidaseMost of the early studies with clorgyline and (-)-deprenyl were performed on either rat brain or liver, where it was shown that 5-hydroxytryptamine was the preferred substrate for MAO-A and benzylamine the preferred substrate for MAO-B, whilst tyramine was found to be deaminated by both enzyme forms (Johnston 1968; Hall et a1 1969). However, this substrate specificity is by no means universal. In Table I, the data published over the last ten years have been investigated in order to determine the frequency of occurrence of the metabolism of a given substrate by a given enzyme form. The 'common substrate' tyramine, for example, is in fact metabolized by both enzyme forms in only 29 out of 51 tissues (see Table I). Most of the possible combinations of the substrate specificities of the two forms of M A 0 have been reported. Some examples of 'unusual' combinations towards three of the most commonly used substrates are shown in Table 2...

Summary and conclusionsThe effect of dieting on blood pressure and catecholamine metabolism was assessed in 11 normotensive obese women by providing first a weight-maintenance regimen high in carbohydrate and then a low-energy diet. All dietary constituents other than carbohydrate were maintained constant throughout the 18-day study. The low-carbohydrate diet led within 48 hours to a 41% fall in the urinary output of 4-hydroxy-3-methoxy mandelate and a significant fall in systolic and diastolic blood pressure. Plasma noradrenaline concentrations also fell and the hypotensive effect of the diet continued despite a maintained total body sodium.Thus the fall in blood pressure appeared to be mediated by changes in catecholamine metabolism independent of sodium intake. This may explain both the usefulness of weight reduction in hypertensive patients and the fainting that occurs in some normotensive obese subjects taking slimming regimens low in carbohydrate. IntroductionThe considerable evidence of a relation between obesity and hypertension has led to the emphasis on maintaining an ideal weight in hypertensive patients. Although the fall in blood pressure that occurs with weight loss' is usually explained by a concomitant reduction in salt intake, Reisin et a12 reported a reduction in blood pressure in obese hypertensive patients on diet even when the salt intake remained unchanged. The underlying mechanisms in the pathogenesis of hypertension are still uncertain but overactivity of the sympathetic system has been implicated in a proportion of cases, since plasma concentrations of noradrenaline, adrenaline, and dopamine-,-hydroxylase have been found to be raised.3-5 This is not a universal finding, however,6 and it is not clear whether any of the reported abnormalities in catecholamine metabolism precede or accompany the development of hypertension. We have therefore attempted to explore some of the mechanisms underlying the control of blood pressure by studying normotensive obese women on a slimming regimen while maintaining their salt intake.

1. The thermogenic response and changes in plasma substrates and hormones were tested after a liquid meal in lean, obese and formerly obese women. 2. Subjects with a family history of obesity tested either while obese or after slimming to a normal weight had a thermogenic response, which was only half that of the lean group. 3. The immediate response in plasma glucose and insulin was greater in the lean subjects, but the sustained changes in circulating substrates did not differ in the three groups. Thyroidal hormone concentrations did not alter postprandially: venous noradrenaline levels rose in the obese groups only. 4. The differences in postprandial thermogenesis at rest would reduce the energy requirements of subjects with familial obesity, but they still had a metabolic rate estimated to be nearly 1MJ (240 kcal)/day in excess of the lean group so additional thermogenic defects must exist for familial obesity to be explained solely on a metabolic basis.

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The p rones, 3-hydroxy-2-methyl-4-pyrone (maltol) and 3-hydroxy-2-ethyl-4-yrone (ethyl complexes, being neutral, are able to partition readily across cell mem ranes and thus may facihtate iron transport across the intestinal wall. Absorption of radioactive iron (59Fe) in the presence of these pyrones was investigated in male rats 1, 2, 4 and 6 h after intraduodenal administration of a 7 pg dose and compared with that of 59Fe given as the sulphate, gluconate, fumarate or complexed to EDTA. Total body absorption and distribution were calculated from the 59Fe content of various tissue samples. With all the iron preparations used, blood levels of 59Fe were highest 1 h after injection whilst the 59Fe content at the major site of deposition, i.e. the bone marrow, increased up to 6 h. No 59Fe was found in the urine. Total body absorption of 59Fe was si nificantly higher from the pyrones than from the other four preparations. Over the cfose range 0-7-700pg, the proportion of 59Fe absorbed from both iron maltol and iron sulphate decreased with increasing dose. Enhanced 59Fe uptake from maltol was evident at 0-7-70 p but not at 700 pg suggesting that use of these pyrones will not result in iron overload. Agsorption of 59Fe given into the stomach was slower in onset but was sustained longer presumably via a steady delivery of iron to the duodenum from the gastric reservoir. The presence of excess maltol to maintain the inte rity of the neutral 1 : 3 iron-maltol complex under a variety Of physiological conditions di c f not appear critical in-vivo for effective iron absorption. There was no difference in 59Fe uptake between maltol, ethyl maltol or a mixture of ethyl maltol and maltol. 59Fe uptake was significantly enhanced in iron-deficient animals. Within 1 min of i.v. injection of iron complexed to maltol or ethyl maltol, 59Fe became associated with a plasma protein of molecular ratio similar to that of transferrin. With EDTA this process was much slower, i.e. up to 60min. The half-life of 59Fe in the blood was similar whether administered as the maltol, ethyl maltol, sulphate or EDTA; at the 110 pg iron dose it was 133 k 8 min and at 1 pg it was 74 k 10min in iron-replete animals and 44 k 5 min in iron-deficient animals. The rate of absorption from the duodenum of 59Fe given as maltol, ethyl maltol or as iron sulphate increased with increasing dose but the shape of the absorption curve depended on the rate of movement of iron along the intestine. It is concluded that the pyrones, maltol and ethyl maltol, are able to enhance the initial sta es of iron uptake from the intestinal lumen, possibly by holding the iron in a readily absoriable form, but do not influence subsequent iron distribution and so may provide safe and palatable alternatives to those iron preparations presently available for the treatment of iron deficiency.

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1. The metabolic response of lean and obese women to caffeine was studied to see if caffeine could be used to demonstrate the subnormal thermogenesis in obesity previously shown after standard meals or intravenous infusions of noradrenaline. 2. The rise in resting metabolic rate with caffeine was similar in the lean and obese groups and beta-adrenoceptor blockade did not reduce the increment in metabolic rate in either group. These responses did not, therefore, correspond with the other subnormal thermogenic responses of the constitutionally obese. 3. In a post-obese group, i.e. previously obese women who were now of normal weight, there was a reduced response of the resting metabolic rate to caffeine. 4. Monitoring plasma substrate concentrations showed that the change in oxygen uptake corresponded to changes in plasma free fatty acids, so that in adults the metabolic effects of caffeine seem to be mediated by increases in adipocyte lipolysis. This effect seems to be mainly independent of the adrenergic system.