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539 Thiamine as a nicotine antagonist
Abstracts of Papers the administration of these two substances. Certain organs become selectively charged: the liver and kidney were wry active; the myocardium, intrascapular fat and the brain retained radioactivity to a lesser extent. (2) In the rat: nleasuremcnts of the radioactivity of thr principal organs (liver, kidney, heart, brain) showed a constantly higher concentration of dithiopropylthiamine than of thiamine. In the liver the radioactivity drcreased with time; in the kidney it remained low ; in the brain and myocardiurn, howevrr. it increased progressively during the course of 24 hr. Excretion in the urine affected dithiopropylthiamine more than vitamin B,, as dithiopropylthiaminc is absorbed to a greater cstrnt by the intestine. C!hromatographic analysis shows that dithiopropylthiaminr is transformed to thiamine in the liver. Conclusion: Comparison of the metabolism of and dithiopropylthe antineuritics thiaminr thiamine leads to the conclusion that the difference in their biological properties is essentially quantitati\-?.
539 Thiamine as a Nicotine I. YAMAMOT o (Japan) .
540 Non-Hvdrazide Monoamine Oxidase Inhibitors and Their Elfects on Central Amines G. M. EVERETT and and Motor Behaviour. K. G. ~VIEGAND (U.S.A.). Two series of non-hydrazide 11.40 inhibitor\ have been investigatrd for pharmacologic responses and biochemical changes. I.evcls of DOP.1. dopamine, norrpinephrine. cpinephrine and serotonin were determined in whole mouse brain afttl giving MAO inhibitors alone or in combination with DOPA. MO-91 1 (A19120) (N-bmzyl-N-methyl-2-propynylamine hydrochloride) is an active hIX0 inhibitor in ho and in C&J. The central amincs gradually increase concomitantly with increasing Thrse rff+xts motor activity and aggressiveness. arc rnhanced after giving DOPA. MO-1255 (A197.57) (ethyl-N-benzyl-N-cyclopropylcarbamatc) appears inactiw by in zsitro tests, but is a potent %%A0 inhibitor in rGo. Its rffcct on central amines are similar to hIO-911. Both 110-911 and MO-1255 are five times more potent than iproniazid as determined by the in ciao DOPA response test in mice. MO-1 255 has a duration of only 3 days as compared to 8 days for iproniazid or bIO-91 I in the mouse. Neither of these new drugs is a direct central stimulant. Nevertheless, after giving the drugs to dogs, cats and monkeys, grad”ally increasing motor activity and irritability develops over a period of a day or more and then slowly subsides. The parallel data on rrntral amincs and behavioural rrsponse suggest a close correlation between dopaminr and norepinephrine levels and increased motor activity and agrrssivenrss.
Antagonist.
I” our serial study on nicotine metabolism and its detoxication, thiamine was proved to be antagonistic to nicotine in various organs in &TO and this antagonism was stronger than that of acetylcholine or histaminr suggesting that one of principal sites of action of thiamine is located in nerve ganglion. From activity-concentration curves, this antagonism appeared to be a so-called competitive 0”~ being more typical tha” those of hcxamethonium and TEA. Thiamine is vasodepressing in dogs and not associated with adrrnergic action but antagonistic to the pressor effect of nicotine and bilateral occlusions of the common carotid. It inhibits the depressor response to vagus stimulation. Thcsr findings and those obtained from experiments on cat nictitating membrane may be taken as iliustrations of a ganglionic blocking effect of thiamine. Thiaminr displayed a supressing effect probably based on the blocked adrenaline release of nicotine, on the nicotine-induced hyperglucaemia in rabbits. Diuresis hy cigarette smoking was significantly inhibited by thiamine in ma” while it exerted no influrnce on the diuresis induced by hypophyseal posterior lobr extract suggesting that nicotine antagonism by thiamine is connected with the hypothalamo-posterior-pituitary system and, furthermore, it is interesting to note that no othrr nicotinolytic substances showed this type of antagonism. Among related compounds to thiamine, thiazole derivatives containing a” amino group at “2” and/ or phenyl group at other than “2” elicited an augmcntation in antagonistic activity to nicotine.
163
54
I
Inhibition tamine
of Dovamine !SOxidase by Amphe_ and p-Hydroxyamphetaxkne. RZ. GOLDSTFJN (U.S.A.).
.4mong several structural analogues of dopamine, amphetamine (phenylpropylamine) and p-hydroxyamphetamine (fi-hydroxyphenylpropylamine) were tested as possible inhibitors of dopamine P-oxidasr. The enzyme dopamine $-oxidase which catalyses thr coIlversion of dopamine to norepinephrinc was prepared from adrrnal mrdulla by the method of Levi” et al.” The relative inhibition rate of dopamine P-oxidase by amphetamine and phydroxyamphetamine was detrrmined by comparing the amSmnts of norepinephrine-1-“C formed in an incubation mixture which contained only the substrate (dopamine-l-‘4Ci and a” incubation mixture which contained the substrate together with or p-hydroxyamphetamine. The amphetamine linear increase of inhibition with the amount of added amphetamine or p-hydroxyamphetamine suggests that these two compounds are in competiIt is tion with the substrate for the same enzyme. likely that the enzyme (dopamine $-oxidase) which has been shown to be non-specific for dopamine12’
539 Thiamine as a Nicotine I. YAMAMOT o (Japan) .
540 Non-Hvdrazide Monoamine Oxidase Inhibitors and Their Elfects on Central Amines G. M. EVERETT and and Motor Behaviour. K. G. ~VIEGAND (U.S.A.). Two series of non-hydrazide 11.40 inhibitor\ have been investigatrd for pharmacologic responses and biochemical changes. I.evcls of DOP.1. dopamine, norrpinephrine. cpinephrine and serotonin were determined in whole mouse brain afttl giving MAO inhibitors alone or in combination with DOPA. MO-91 1 (A19120) (N-bmzyl-N-methyl-2-propynylamine hydrochloride) is an active hIX0 inhibitor in ho and in C&J. The central amincs gradually increase concomitantly with increasing Thrse rff+xts motor activity and aggressiveness. arc rnhanced after giving DOPA. MO-1255 (A197.57) (ethyl-N-benzyl-N-cyclopropylcarbamatc) appears inactiw by in zsitro tests, but is a potent %%A0 inhibitor in rGo. Its rffcct on central amines are similar to hIO-911. Both 110-911 and MO-1255 are five times more potent than iproniazid as determined by the in ciao DOPA response test in mice. MO-1 255 has a duration of only 3 days as compared to 8 days for iproniazid or bIO-91 I in the mouse. Neither of these new drugs is a direct central stimulant. Nevertheless, after giving the drugs to dogs, cats and monkeys, grad”ally increasing motor activity and irritability develops over a period of a day or more and then slowly subsides. The parallel data on rrntral amincs and behavioural rrsponse suggest a close correlation between dopaminr and norepinephrine levels and increased motor activity and agrrssivenrss.
Antagonist.
I” our serial study on nicotine metabolism and its detoxication, thiamine was proved to be antagonistic to nicotine in various organs in &TO and this antagonism was stronger than that of acetylcholine or histaminr suggesting that one of principal sites of action of thiamine is located in nerve ganglion. From activity-concentration curves, this antagonism appeared to be a so-called competitive 0”~ being more typical tha” those of hcxamethonium and TEA. Thiamine is vasodepressing in dogs and not associated with adrrnergic action but antagonistic to the pressor effect of nicotine and bilateral occlusions of the common carotid. It inhibits the depressor response to vagus stimulation. Thcsr findings and those obtained from experiments on cat nictitating membrane may be taken as iliustrations of a ganglionic blocking effect of thiamine. Thiaminr displayed a supressing effect probably based on the blocked adrenaline release of nicotine, on the nicotine-induced hyperglucaemia in rabbits. Diuresis hy cigarette smoking was significantly inhibited by thiamine in ma” while it exerted no influrnce on the diuresis induced by hypophyseal posterior lobr extract suggesting that nicotine antagonism by thiamine is connected with the hypothalamo-posterior-pituitary system and, furthermore, it is interesting to note that no othrr nicotinolytic substances showed this type of antagonism. Among related compounds to thiamine, thiazole derivatives containing a” amino group at “2” and/ or phenyl group at other than “2” elicited an augmcntation in antagonistic activity to nicotine.
163
54
I
Inhibition tamine
of Dovamine !SOxidase by Amphe_ and p-Hydroxyamphetaxkne. RZ. GOLDSTFJN (U.S.A.).
.4mong several structural analogues of dopamine, amphetamine (phenylpropylamine) and p-hydroxyamphetamine (fi-hydroxyphenylpropylamine) were tested as possible inhibitors of dopamine P-oxidasr. The enzyme dopamine $-oxidase which catalyses thr coIlversion of dopamine to norepinephrinc was prepared from adrrnal mrdulla by the method of Levi” et al.” The relative inhibition rate of dopamine P-oxidase by amphetamine and phydroxyamphetamine was detrrmined by comparing the amSmnts of norepinephrine-1-“C formed in an incubation mixture which contained only the substrate (dopamine-l-‘4Ci and a” incubation mixture which contained the substrate together with or p-hydroxyamphetamine. The amphetamine linear increase of inhibition with the amount of added amphetamine or p-hydroxyamphetamine suggests that these two compounds are in competiIt is tion with the substrate for the same enzyme. likely that the enzyme (dopamine $-oxidase) which has been shown to be non-specific for dopamine12’