Acid Diethylamide Research Articles

Lysergic Acid Diethylamide (LSD-25) Antagonists

A. Introduction It has been shown1,2that 2 mg. of crude beef brain extract per milliliter of water blocks the usual effect of 2μg of LSD-25 per milliliter in the outside liquid on the Siamese fighting fish.* The experiments to be reported here are the study of a blocking effect probably produced by another mechanism: the development of tolerance3to LSD-25 in man by the prior administration for a period of days of a compound similar to LSD-25. This compound, 1-methyl-d-lysergic acid diethylamide (MLD-41), produces in man reactions indistinguishable from LSD-25 but has a higher reaction threshold. It will be shown on the basis of our data that MLD-41 affects both the Siamese fighting fish and man in a manner similar to LSD-25. However, there are important differences; in the fish it is about 1/10 as effective as LSD-25, whereas it is approximately 1/3 as effective in man.

クマリン誘導体の薬品的研究 (第9報)

4-Methylcoumarin, which has been found by past studies to possess comparatively good hypnotic activity and which shows hypnotic state symptomatically the same as that of barbital when administered to mice, and coumarin-3-carboxylic acid diethylamide, which shows hypnotic state different from that of barbital, were chosen to make a comparative examination of the hypnotic efficacy of these two derivatives and of barbital by the six-point assay method of parallel line assay. The result obtained was barbital=l>coumarin-3-carboxylic acid diethylamide=0.5767>4-methylcoumarin=0.52545. The safety index used to show the safety of pharmaceutics to date included (1) LD50/ED50 or ED50/LD50 and (2) SSM=(LD1/ED99-l)×100, the standard safety margin proposed by Foster. However, (1) gives no considerations for the distribution of ED and LD, while that is taken care of in (2) but extreme values such as LD1 and ED99 are estimated and goes contrary to the adoption of ED50 and LD50 proposed because the estimation of the values of LD1 and ED99 is too difficult. It is, therefore, proposed that a new safety index (Is) be adopted which would be represented by Is=1/σED (logLD5-logED50)=bED (XLD50-XED50), in which ED50 is taken for the effective dosis, bED as its distribution, and the more easily estimable LD5 as the lethal dose.The safety indices for the foregoing three compounds were calculated and their safety was comparatively examined.

Coumarin-3-carboxylic Acid及び3, 4-Dihydrocoumarin-3-carboxylic Acidの塩基性誘導体の合成

Being interested in the physiogical proparties of coumarin-carboxylic acid derivatives, following were synthesized: Coumarin-3-carboxylic acid dimethyl amide (m.p. 145°) and its 3, 4-dihydro derivative (m.p. 75°); coumarin-3-carboxylic acid diethyl amide (m.p. 78°) and its 3, 4-dihydro derivative (b.p.7 143°); β-dimethylaminoethyl coumarin-3-carboxylate (m.p. 82°) and its 3, 4-dihydro derivative (b.p.0.3 87°, picrate, m.p. 137° (decomp.)); β-diethylaminoethyl coumarin-3-carboxylate (m.p. 68°) and its 3, 4-dihydro derivative (b.p.0.9 89°, dipicrolonate, m.p. 141° (decomp.)). Their physiological properties are still under investigation.

化學構造上メチル基及びエチル基の相違と藥理學的作用との關係について 特にN-原子に結合せる兩基の比較

In order to determine the differences in effect of methyl and ethyl radicals in pharmacological actions, I compared compounds having one, two, or three methyl radicals with those in which the methyl radicals had been substituted with the ethyl radicals respectively and vice versa. Results : (1) For comparing the differences in effect of methyl and ethyl radicals in compounds having single methyl or ethyl radical, I have chosen meperidine hydrochloride (a), an analgesic, and a compound (b) which was obtained by substituting the methyl radical attached to nitrogen of the meperidine hydrochloride with an ethyl radical. No qualitative differences were observed. However, the action of (b) appeared to be slightly weaker than that of (a) as shown by LD50 in mice and the tests for analgesic action by the hot plate method and the respiratory depressant action in rabbit by the Wright's respiratory apparatus. (2) As an example of compounds having two methyl and ethyl radicals, the respiratory stimulants, coramine (nikethamide) (c) and cycliton (e) were compared with compounds derived from them by the substitution of the ethyl radicals by the methyl radicals respectively (d, f). Not only considerable quantitative differences were observed in LD50 in mice, minimal convulsive doses and, in respiratory stimulant action, but also qualitative differences were observed. Where as (c) and (e) had only stimulant action, (d) and (f) had depressast action in small dosage and stimulant action in large dosage. As a further example the sedatives, coumarine-3-carboxylic acid diethylamide (g) and its methyl substituted coumarine-3-carboxylic acid dimethylamide (h) were compared (h) was weaker in hypnotic action but was more toxic. Qualitative differences were also observed in the respiratory stimulant action and in the convulsive state. (3) As an example of three methyl and ethyl radicals, carbaminoyl choline chloride (i) was compared with a compound derived from it by the substitution of its three methyl radicals by three ethyl radicals (j). Althoush (i) exhibited series of actions observable when three parasympathetic nerve is stimulated. (j) had none of such actions. Also difference in LD50 in mice of (j) and (i) was very great, (j) being 200 times that of (i).