The inhibition of acetylcholinesterase by nicotinic acid derivatives presented a strong evidence to the supposition of Bergmann, Wilson and Nachmansohn (1) and Wilson (2) that there exists a basic group in the esteratic site of the cholinesterase.
They supposed that a covalent bond was formed between the carbonyl carbon atom of the inhibitors and the nucleophilic center of the enzyme, e.g. the basic group of the esteratic site, because the order of inhibitory strength of these derivatives is consistent with that of electrophilic character of the carbonyl carbon. Fig. 1 shows the chemical structure of nicotinic acid derivatives they used.
They estimated the order of electrophilic properties of each substituent by the order of Hammett's para sigma constant (3) and also by that of the inductometric polarizability.
There is, however, a question whether it might be quite right to assume a hypothesis that the effect of a substituent adjacent to the carbonyl carbon atom is identical to that of the substituent of the para position in the benzene ring.
Furthermore, Hammett's constant of the diethylamino group seems rather too large as compared with that on the Jaffe's table (see the numerals in the parenthesis in Table 1)(4, 5).
Whether the inductometric effect might be large enough to reverse the former effect or not can not be also easily answered.
For these reasons it is favorably considered to treat this problem more quantitatively from the quantum chemical view point. So the author calculates the magnitude of the electrophilic properties of the carbon atom of nicotinic acid derivatives by the simple LCAOMO method and finds that their order is almost parallel to those of Bergmann et al. With some exceptions some other possibilities are, however, suggested.

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The depression of the spontaneous movement of mice by xylopinine, 2, 3, 10, 11-tetramethoxy-5, 6-13a-tetrahydro-8-dibenzo(a-g)quinolizinc, has been reported by Nakanishi (1). In the unanesthetized rabbit, the intravenous injection of xylopinine produced high voltage slow waves and increased spindle waves in EEG. The threshold voltage for eliciting the reticular arousal response by stimulation of the ascending reticular formation was also elevated.
Recently, Hsu and Kin (2) have studied the pharmacological effects of tetrahydropalmatine and its analogues. They showed that tetrahydropalmatine exerted sedativetranquilizing effects in mice.
The present experiments were designed to study sedative-tranquilizing effects of xylopinine in mice.

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Serial studies have been brought about on the nicotine detoxication with special reference to the metabolic fate of nicotine (1-7) and also on the action mechanism of nicotine antagonists (8-12) by Yamamoto and his coworkers since 1951. The fact that thiamine possessed an antagonistic action on nicotine toxicity was firstly pointed out by Unna et al. in 1944 (13) and the present author found also that thiamine inhibited selectively the action of nicotine as well as nornicotine in vitro.
The present experiment was aimed to elucidate the antagonistic mechanism between thiamine and nicotine, and also to investigate the structure-activity relationship of various thiamine related compounds.

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Schon früher haben Gibbs u. Mitarb. (1, 2) von periodischen Veränderungen der elektrischen Aktivität des Cortex, die zeitlich den Atembewegungen entsprachen, berichtet. Jedoch konnten sic die Beziehungen zwischen elektrischer Aktivität des Zentralnervensystems and der Atmung nicht klären. Wir haben kiirzlich darüber berichtet (3), dass die Steigerung der elektrischen Aktivität der Grosshirnrinde (Neocortex) bei Hypoventilation wahrscheinlich auf einer Aktivierung des Atemzentrums beruht, doch konnte die Beziehung zwischen beiden Vorgängen nur zum Teil geklärt werden. Es wird nun von Versuchen berichtet, die uns der Beantwortung jener Frage naher bringen sollten.

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Cyclic derivatives of barbiturates (1, 2), hydantoins (3, 4), oxazolidines (5, 6), succinimides (7) and straight-chain derivatives of phenylacetylurea (8-10) have widely been used as the therapeutic antiepileptics. Phenylacetylurea (phenurone) was introduced by opening the hydantoin ring. The compound has been shown being a unique anticonvulsant for the treatment of the psychomotor epilepsy which had been relatively refractory to the other antiepileptics (11, 12). However, a number of side effects such as gastrointestinal disturbance, hepatotoxicity and personality disturbance, all inherent to the compound have limited the clinical use (11, 13). Further studies for the elimination of the side effects of the phenurone have introduced pheneturide (9) and N-acetyl pheneturide (crampol) (10) which still showed some similar side effects.
Looking for less toxic and more effective anticonvulsant extensive studies of a series of allophanate compounds have chemically and pharmacologically been in succession in this laboratory. Among the derivatives studied, ethyl α-phenylbutyroyl allophanate (P-5257) has proved considerably unique in the anticonvulsant activity being highly potent, longer-durating and less toxic. The pharmacological effects of the compound compared with those of the derivatives of phenurone are described in the present report.

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The studies of Schmitterlow (1) have indicated that the noradrenaline-like vasopressor substances were to be present in extracts from blood vessels. Burn and Rand (2, 3) confirmed that in the walls of arteries there was an appreciable amount of noradrenaline and that it was depleted by reserpine pretreatment as catecholamines in other organs. Maxwell et al. (4), Schmidt and Fleming (5) and Trendelenburg et al. (6) showed that the response to sympathomimetic amines was altered after the subjects had been treated with reserpine. It is suggested that the mode of action of these amines on vascular smooth muscle may be modified by the changes of the amount of noradrenaline stores in the tissue.
In the present experiments the sensitivity to noradrenaline and tyramine was investigated by using smooth muscle strips prepared from various regions of the vascular system. The difference of the sensitivity was discussed with reference to the concentrations of noradrenaline present normally, depleted with reserpine, or absent inherently.

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Recently, reports have appeared, which indicate that the positive inotropic action of catecholamines on the heart is closely related to an activation of the cyclic 3', 5'-AMP formation with the subsequent conversion of phosphorylase b to a. Kukovetz et al. (1) and Hess et al. (2) noted a positive correlation between the increased force of cardiac contraction produced by sympathomimetic amines and phosphorylase a activity. Mayer and Moran (3), Belford and Feinleib (4) and Lacroix and Leusen (5) have published extensive studies on the relationship between the contractile force and the enzyme activity of the heart muscle in vivo and in vitro.
Other reports have given indications that there is no relationship between increased force of contraction and phosphorylase a in the heart. Mayer et al. (6) have recently reported that intravenous injection of adrenaline (0.5 μg/kg) does not produce significant change in the heart phosphorylase a but produces marked positive inotropic effect in the open-chest dog. Considering that cardiovascular reflexes and neurohumoral factors may affect the heart phosphorylase in the open-chest animal (7), Hess et al. (8) have studied the role of the autonomic nervous system in the regulation of heart phosphorylase in the open-chest rat, and showed that cholinergic stimulation of the heart decreases the enzyme activity. Vincent and Ellis (9) have concluded that acetylcholine opposes the glycogenolytic action of adrenaline, since simultaneous infusion of acetylcholine and adrenaline results in no increases in glycogenolysis, and in a marked reduction of chronotropic and inotropic action of adrenaline. Murad et al. (10) confirmed an inhibitory effect of acetylcholine and carbachol on the cyclic 3', 5'-AMP formation in the dog and rabbit heart. If it is certain that the formation of cyclic 3', 5'-AMP is affected by the infused acetylcholine, the endogenous acetylcholine released by a number of agents into the circulating blood may also influence the activity of phosphorylase a in the heart.
It is the purpose of this paper to report the intravenously administered adrenaline on the activity of heart phosphorylase in the open-chest rat.

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In our previous paper it was described that an amino acid, L-dopa (3, 4-dihydroxyphenylalanine) was accumulated in brain slices against concentration gradient and an energy dependent active transport process was assumed to be participated in this phenomenon (1, 4). The carrier system for this active transport of L-dopa was assumed to divide at least into two parts: a specific site to combine with L-dopa and the Na⁺, K⁺-activated ATP-ase which seems to play a common important role for many active transport processes. Moreover it was discussed on a role of intracellular K⁺ concentration in this active transport process (1-4).
In this paper, effect of alcohol on accumulation of dopa in brain slices is examined, for alcohol is a typical neurotropic and lipotropic agent and it is assumed that alcohol may exert a certain influence on the phenomenon and it may be possible to get a clue to clarify a mode of action of alcohol on nervous system.

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It was shown in our previous paper (1) that protoveratrine and EDTA caused a remarkable increase in passive permeability of the membrane of brain slices to cations and this increase was completely prevented by so-called stabilizers such as cocaine and calcium ion. Protoveratrine and EDTA are known to be depolarizers (2) and the effects of these drugs on brain slices were considered to represent a model of natural excitation of the nerve cell membrane.
An increase in respiration of brain slices by protoveratrine has been already reported by several investigators (3, 4). In this paper effects of protoveratrine, EDTA and cocaine on respiration and energy metabolism of brain slices are examined to know a relation between changes of membrane structure resulting in an increase in permeability and energy metabolism connected with it.

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It has generally been accepted that the vagal effect participates in bradycardia due to cardiac glycosides (1, 2). However, the vagal effect may not be the only factor which produces the cardiac slowing, because cardiac glycosides can produce bradycardia even after bilateral severance of vagus nerves or under the effect of atropine (3, 4). Gold et al. (5, 6) suggested a direct bradycardiac action of cardiac glycosides on the heart muscle. However, the results on the effect of cardiac glycosides on the heart rate are still controversial in the experiments with isolated hearts. Heymans et al. (7, 8) reported that cardiac glycosides did not produce bradycardia in dogs when vagus nerves and also carotid sinus nerves were completely severed. The present author has also obtained a similar finding in cats using a cardiac glycoside, strospeside (9).
In recent work of the present author (9), a hypothesis has been postulated on the mechanism of bradycardia produced by cardiac glycosides: There are two different kinds of nervous reflex systems, quite independent of each other, in producing bradycardia by cardiac glycosides. One is the vago-vagal reflex and the other is the carotid body-sympathetic nervous reflex chain possibly composed of the sinus nerve, cervical cord, stellate ganglion and the sympathetic fibers to the heart.
The purpose of the present experiment is the presentation of some evidences for the possibility of the sympathetic portion of the hypothetical carotid body-sympathetic nervous chain, which is assumed to be the extravagal factor, by observing the effect of strospeside on the efferent discharges in the cardiac sympathetic nerves in cats.

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