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iprr*** >^-LV v ' o Page Two sociated with brain metabolism and, possibly, upon other pertinent bio- chemical systems^ in vitro . Based on the information available at the pre- sent tine, the systems listed below are being considered for the first se- ries: of evaluative experiments. While we realize that their causal* connec- tion wi"h halucinatory disturbances has not been conclusively established, we feel that they constitute a suitable starting point. In each instance, known psychotomimetic agents will be evaluated elong with our compounds, (^'cholinesterases: a. acetylcholinesterase (substrate! acetyl-*—methyl choline; compounds studied: pyridine- and piperidinecarboxylic acid, erylallcylanine and indolylalkyl amine derivatives^ effects studied: inhibition and/or potentiation; method: VJarburg manometrie technique) b. ps e ud ocholin es teres e (substrate: butyryl choline and/or bensoylcho- line; compounds studied: pyridine- and piperidinecarboxylic acid, arylalkylr-mine and indolylalkylaiaine 'derivatives; effects studied: inhibition and/or potentiation; method; Warburg nanometric technique) LSD was found to be a powerful inhibitor of pseudccholinesterase in hirzan serum and brain. Pseudocholinestere.se activity of rat, guinea-pig, rabbit, . chicken and nonkey brain is much less sensitive to inhibition bjT LSD than is the corresponding enzyme in human brain. ^Pseudocholinesterase was in- hibited more powerfullylbylLSD than by other ergot alkaloids. (R. H. S. Thompson, A. Tickiier and G. R^Webster, Brit, J. Pharmacol., 10: 6l, l?p5. )- LSD was found to inhibith(5>05») ps eudocholincsterc se activity at a 1x10”® M« concentration and was found to augnent_(5C5*)-the activity of the enzyme at 6x10 M. concentration. Siniler observations were reported for serotonin ( 5“hyd roxy tryptani ne ) . (G. H, Fried and W. Antopol, Fed. Proc., 16: Meperidine (l-methyl-^-phenyl-ti-carbethoxypiperidine) and other mrcotic analgesics capable of producing hallucinations were reported to potentiate (42-15SJ») the hydrolysis of benzoyl choline by pseudocholinesterase at con- centrations ranging from 1CT' to lCT*4 M, (S. G. Erdos and S, P. Shan or. Fed, Proc., 16: ?31t l?p7*)- Tryptomine' and benzyl r-~: no (phenylnethylanine) were found to activate (4*»-9p£j) the hydrolytic action of pseudocholinesterace upon benzoylcholino, (E, G, Erdos, F. F. Foldcs, l. T » Eaart end S. P, Shanor, Fed. Proc., 16: 2J»4, 1557^ amine oxidases: a ? ponox-ino oxi dase end b. d iamine oxidase (substrate: arylalkylmine and indolylalkylanine derivatives; compounds studied: known end potential inhibitors, our pyridine- and piperidinecarboxylic acid derivatives; ..effects studied: inhibition and/or potentiation, evaluation of relation- ships in the substrate affinities of the two enzymes; method: Y’erburg nanoaetric technique) Monoamine oxidase is considered to be a major catalyst of serotonin metabo- lism in tissues. Iproniazid is reported to inhibit monoamine oxidase in tho brain, but unable to penetrate to the site of r.onoenine oxidase in intact cells of other tissues. (H. Vcisrbach, D. F. BogdaneM, B, Redfield end S. Udenfriend, Fed. Proc., 16: ^*5, )- Relationships between monoamine oxidase end diamine oxidase were reported. There is indication that the af- finities of the two enzymes are overlaping; however, sor.e of their characte- ristics have been found to retain their specificities. Mescaline (5,4,5-tri- nethoxyphenethylRnine) ar.d tyranine were reported to be among the substrates of diamine oxidase, while some JS-arsinoethyl imidazoles were found to be sub- strates for Eonoe-rine oxidase. (E, A, Zeller, J. Earsky, L, A, Eleoiksma, and J. C. Lzzanas, Fed, Proc., 16: ZJ6, 1957«)- Ssccharonyces cerevisiae: 3. cercvi siae (substrate: glucose; compounds studied: pyridine- end pipe- ( 2 ) (5)