A series of 1,2,3,4-tetrahydro-, 3,4-dihydro-, and fully aromatic isoquinolines were tested as substrates and/or inactivators of highly purified human monoamine oxidase A and B (MAO A and B). None were found to be a substrate for either enzyme, but many of these isoquinolines could selectively inhibit either MAO A or B. Stereoselective competitive inhibition of MAO A was found with the R enantiomer of all the stereoisomers tested, including salsolinol (Ki = 31 microM), salsoline (Ki = 77 microM), salsolidine (Ki = 6 microM), and carnegine (Ki = 2 microM). As a class, the 3,4-dihydro-isoquinolines were the most potent inhibitors tested (Ki = 2-130 microM), and the fully aromatic isoquinolines had intermediate activity (Ki = 17-130 microM) against MAO A. In contrast, only a few of these compounds markedly inhibited MAO B. 1,2,3,4-Tetrahydroisoquinoline, its 2-methyl derivative, and o-methylcorypalline gave apparent Ki values of 15, 1, and 29 microM, respectively, and two 3,4-dihydroisoquinolines (compounds 22 and 25) showed substantial inhibition of MAO B (Ki = 76 and 15 microM, respectively). These results support the concept that the topography of the inhibitor binding site differs in MAO A and B.

The neurotoxm I-methyl-4-phenyl-1,2,3,6-tetrahydropyrldlne (MPTP)

Unilateral intranigral administration of the oxidative metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-dihydropyridine (MPDP+) or 1-methyl-4-phenylpyridine (MPP+) produced dose-dependently a depletion of dopamine in the ipsilateral striatum of rats two weeks following treatment. d-Amphetamine and apomorphine induced circling toward the lesioned side in these unilaterally treated animals. No contralateral circling behavior was observed after challenging with apomorphine. This dopamine lesioning effect of MPP+ was not blocked by pretreatment of animals with a dopamine uptake blocker, GBR 12909. Furthermore, MPP+ increased the 45Ca accumulation into cells at the site of injection and produced "nonspecific" cell membrane and/or cytotoxic damage seen by histological procedures. These results indicate that MPDP+ and MPP+ produced localized cytotoxic damage to nigrostriatal neurons, caused a decrease in striatal dopamine, and disrupted the nigrostriatal system's functioning following intranigral administration to rats. It is postulated that the cationic surfactant properties of MPDP+ and MPP+ might contribute to its neurotoxic effects.

The P-carbolines flazin (1) and perlolyrine (2, substance YS) occuring in J apanese sake and soy sauce were synthesized starting with the methyl ester of L-tryptophan or tryptamine, respectively. The inhibition of the monoamine oxidases A and B by 1 and 2 were determined and compared with theinhibitory effects of harmine and harmaline. 0-Carboline aus japanischem Sake und aus Soya-Sauce: Synthese und biologische Aktivitat des Flazins und der gelben Substanz YS (Perlolyrh) ~i~ p-Carboline plazin (1) und Substanz ys = perlolyrinis (2), die in japanischem Sake und japanischer s~~~. s~~~~ vorkommen, wurden ausgehend von L-Tryptophanmethylester respektive Tryptamin synthetisiert. Die Hemmung der Monoaminoxidasen A und B durch 1 und 2 wurde im Vergleich mit Harmin und Harmalin gemessen.The highly fluorescent P-carbolines flazin and substance YS, isolated from Japanese soy sauce, were reportet to have structures 1 and 2 respectively'). Both compounds also occur in Japanese saks), and 2 seems furthermore to be identical with the alkaloid perlolyrine isolated from ryegrad). Perlolyrine (2) was synthesized from (+)-tryptophan and its structure confirmed by an X-ray analysis of its hydrobromideg). Flazin methylester (7) prepared by the Japanese investigators from flazin (1) with diazomethane') is structurally related to 3-(ethoxycarbonyl)-P-carboline (CEE) which strongly binds to benzodiazepine receptors4) and has for this reason aroused considerable interest. Perlolyrine (2), on the other hand, is structurally related to the Harmalu alkaloid harmine, a known inhibitor of monoamine oxidase As). The presence of 1 and 2 in food and their chemical relationship to well known psychomimetics provided incentive to prepare them in sufficient quantity for testing.The route chosen by us resembles in principle the reported synthesis of Z3), obtained from (+)-tryptophan by PictetSpengler reaction with 5-(acetoxymethyl)furfural, and followed by oxidation of the reaction products with chromic acid3), but varies in details.Direct condensation of L-tryptophan with commercially available 5-(hydroxymethy1)furfural 6, did not readily yield the desired tetrahydrocarbolines. However, success was achieved when the methyl or ethyl ester of L-tryptophan was reacted with 5-(acetoxymethy1)furaldehyde in refluxing benzene in the presence of a catalytic amountof p-toluene-sulfonic acid to yield Schiff base 3, which cyclized spontaneously to a 3 5 mixture of cis-and trans-tetrahydrocarbolines 4 and 5, respectively. The mixture could be separated by column chromatography and configuration of the two compounds was established on the basis of C-13 NMR data7! Aromatization of 4 and 5 with Pt/C catalyst in the presence of oxygen afforded the desired carboline 6, with a faster aromatization rate noted for trans isomer 5. Removal of the acetyl group in 6 with 0.5 % NH40H in methanol led to compound 7, identical with flazin methylester '). Hydrolysis of 6 in 0.1 N methanolic NaOH yielded a yellow, crystalline product, identical with flazin 1'). Attempts to ...